Magnesium Research 2006; 19 (3): 199-215
Ageing, hippocampal synaptic activity and magnesium J.M. Billard Neurobiologie de la Croissance et de la Sénescence, UMR 549 INSERM, Faculté de Médecine, Université Paris-Descartes, IFR Broca-Sainte Anne, 2 ter rue d’Alésia, 75014 Paris, France
Correspondence: J.M. Billard. Tel: (+00 33) 1 40 78 86 47; fax: (+00 33) 1 45 80 72 93 <email@example.com>
Abstract. Ageing is associated with a general decline in physiological functions. Amongst the different aspects of body deterioration, cognitive impairments, and particularly defects in learning and memory, represent one of the most frequent features in the elderly. However, a great variability exists among aged subjects. Clinical reports and experimental data in animal models of ageing have shown that age-associated memory deficits are broadly identical to those induced by damage to the hippocampus. It is therefore not surprising that many functional properties of hippocampal neuronal networks are particularly altered with ageing. Whereas passive membrane properties of neurons are conserved with age, neuronal excitability is altered, in keeping with weaker performances of aged subjects in memory tasks. Synaptic transmission within hippocampal networks also decreases in brain ageing. Deficits concern both glutamatergic and cholinergic pathways, which represent the main excitatory neurotransmitter systems responsible for neuronal communication in the hippocampus. In addition, long-term changes in synaptic transmission, possible cellular substrates for learning and memory, are also impaired in ageing in correlation with cognitive impairments.Neuronal properties and synaptic plasticity closely depend on ion exchanges between intra- and extracellular compartments. Changes in ion regulation during ageing may therefore participate in altering functional properties of neuronal networks. Calcium dysregulation has been extensively investigated in brain ageing but the role of magnesium has received less attention though ageing constitutes a risk factor for magnesium deficit. One of general properties of magnesium at presynaptic fibre terminals is to reduce transmitter release. At the postsynaptic level, it closely controls the activation of the N-methylD-aspartate receptor, a subtype of glutamate receptor, which is critical for the expression of long-term changes in synaptic transmission. In addition, magnesium is a cofactor of many enzymes localized either in neurons or in glial cells that control neuronal properties and synaptic plasticity such as protein-kinase C, calcium/ calmodulin-dependent protein kinase II and serine racemase. It is therefore likely that a change in magnesium concentration would significantly impair synaptic functions in the aged hippocampus. Experiments addressing this question remain too scarce but recent data indicate that magnesium is involved in age-related deficits in transmitter release, neuronal excitability and in some forms of synaptic plasticity such as long-term depression of synaptic transmission. Further studies are still necessary to better delineate to what extent magnesium contributes to the impaired cellular mechanisms of cognitive functions in the elderly which will help to develop new strategies to minimize age-related memory declines. Key words: ageing, hippocampus, magnesium, memory, synaptic plasticity, long-term potentiation, long-term depression
In the last fifty years, progress in the prevention and the treatment of illnesses, as well as the constant improvement of hygiene and nutrition conditions, have increased ageing of the world population and particularly in industrialized countries . Unfortunately, this increase in life duration is generally associated with a progressive deterioration of body systems and functions. Not only reproduction and motor functions are concerned but also mental defects, including deficits in learning and memory (cognitive) or in motivation (emotional) frequently occur with advanced age . One striking feature of ageing is that the degree of cognitive impairment can greatly vary across individuals, from a mild deficit, initially referred as age-associated memory impairment (AAMI)  to a severe dementia. A wealth of data has accumulated indicating that obvious alterations in the central nervous system (CNS) occur in dementia-associated memory declines. For instance, extracellular b-amyloid plaques and intracellular neurofibrillar tangles are salient brain features of Alzheimerâ€™s disease [4, 5]. Regarding the milder deficits in AAMI as compared to dementia, it is likely that brain alterations are much more subtle , even cognitive capabilities are impaired enough to significantly disturb the quality of life of the elderly. A major constraint for the determination of cellular substrates of AAMI is the invasive nature of experiments, which led to the development of animal models of ageing [7-14]. Over the past decades, extensive behavioural experiments, mainly performed on rodents, investigated how the efficient learning and memory in young individuals is slowed down with age, whilst forgetfulness is accelerated [15-23]. In these studies too, the degree of memory decline shows significant variability from one animal to another as it does in the elderly human, allowing tight correlations between anatomical and functional changes in brain ageing and memory deficits. Such correlative studies have been of particular importance to significantly improve our understanding of the cellular basis of AAMI. Experiments on brain ageing have largely been focussed on the hippocampus, a cytoarchitectonally well-defined structure of the limbic system. Several lines of evidence suggest that this structure is a privileged brain target for ageing processes: hippocampal integrity is critical for some forms of learning and memory [24-32] and deficits induced by damage to the hippocampus broadly resemble impairments associated with ageing [33-36]. Moreover, the functional plasticity of neuronal networks, which is proposed as a cellular mechanism critical for memory formation [37-40], was initially described and then
fully characterized in the hippocampal formation [41-44]. Over the last forty years, hippocampal changes in brain ageing have extensively and differently been evaluated and, as expected, a substantial number of alterations detailed and correlated with memory impairments (for reviews see [45-50]). Which exact mechanisms govern these alterations now represents a major challenge for scientists aiming at reducing the occurrence or the magnitude of AAMI. Among other possibilities, the age-related dysfunction of hippocampal activity could be the consequence of changes in ion regulation  since cellular excitability, transmitter release and synaptic plasticity are closely dependent on ion flux across neuronal membranes. Regarding this issue, the role of divalent cations in brain ageing has been very differently addressed. Calcium homeostasis gathered the largest interest with the calcium dysregulation hypothesis of brain ageing in the mid-80s [52-55]. According to this hypothesis, multiple calciumdependent processes change with ageing [56-59]. In contrast, the contribution of magnesium was much less addressed although magnesium is the most abundant divalent cation found in the body with a relative large concentration in the CNS . Moreover, ageing is a risk factor for magnesium deficit that may be induced from two etiological mechanisms: deficiency or depletion (for a review see ). Although brain magnesium content is relatively stable in animal models of hypomagnesemia [60, 62], a significant decrease is found in age-associated neurodegenerative diseases . In addition, magnesium deficit induces specific impairments of emotional memory  indicating that this cation may indeed play a significant role in the physiopathology of AAMI. The goal of this review is to present the current knowledge on the age-related functional alterations of hippocampal networks that may account for AAMI. In addition, experimental results are presented and discussed to determine whether magnesium is concerned in these alterations, leading to the search for new relevant therapeutic strategies to minimize cognitive deficit in the elderly.
Age-related changes in neuronal properties Whether functional properties of hippocampal networks are affected with age has been addressed in the different subregions of the hippocampus using electrophysiological recording techniques mostly performed in slice preparations, although some
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studies have also investigated neuronal firing rates in vivo [65-67]. Basic membrane and cellular properties of hippocampal neurons including resting membrane potential, membrane time constant, input resistance and action potential height and width do not change with age [68-81]. In some studies however, the resting membrane potential of ageing neurons appears more hyperpolarized than that of young neurons [82, 83]. In contrast, ageing alters neuronal excitability: aged neurons display a lower ability to elicit action potentials [74, 75, 77, 81, 83], indicating that sodium channels involved in spike generation are impaired . The calcium-dependent post-burst afterhyperpolarization (AHP) is another critical component of neuronal excitability, limiting the rate of repetitive discharges in response to a sustained depolarisation [85-88]. AHPs are reversibly depressed by the acquisition of hippocampus-dependent behavioural tasks such as trace eyeblink conditioning or spatial water maze [89-91]. Increase in neuronal excitability has therefore been proposed as a possible cellular substrate of learning and memory . AHPs are enhanced with age [56, 72, 76, 83, 92] (and see review in [48, 58]) although this result has not been fully confirmed [75, 77]. The age-related facilitation of AHPs results from a greater expression of L subtype calcium channels by aged neurons [93-95] with increased calcium conductances across the cell membrane [73, 75, 77, 82, 92, 93]. Age-related enhancement of AHPs and increase in the density of L-type calcium channels correlate with memory deficits [92, 96, 97] and pharmacological treatments, reducing AHPs in aged animals, prevent memory decline [98, 99]. In light of these data, a decrease in neuronal excitability may be a substantial cellular cause in the physiopathology of AAMI . A role for magnesium in the age-related alteration of neuronal excitability has not yet been formally demonstrated although indirect evidence suggests that it may be involved in this deficit. Frequency potentiation (FP) represents an increase in synaptic transmission that develops during a train of electrical stimulations . FP is dependent on cell firing and is negatively correlated to AHP magnitude . Due to the enhanced AHP limiting the cell discharge, FP is reduced by age [102-105] but elevating magnesium to calcium ratio counteracts the deficit [104, 105]. This result strongly suggests that the facilitation of calcium conductances carrying the increase in AHP and consequently the decrease in neuronal excitability of aged neurons, is not only due to a greater density of calcium channels on cell mem-
brane as initially proposed [93, 95, 97, 101]. Alternately, a weaker competition between divalent cations due to magnesium deficit would also enhance single calcium channel activity. However, this hypothesis remains to be definitively confirmed; for example, by determining how the enhanced AHP magnitude in aged neurons behaves after altering magnesium to calcium ratio. Age-related changes in synaptic transmission Glutamate is the neurotransmitter involved in most of excitatory synapses in the CNS [106-108]. This is particularly salient in the hippocampus where synaptic activity of cortical afferent systems, including the perforant pathway and commissural fibres, as well as the neuronal communication within intrahippocampal networks requires the release of glutamate [109-111]. Trying to determine whether mechanisms regulating extracellular concentration of glutamate are affected by age has led to divergent results in vitro (for a review see ) whereas experiments conducted in vivo report an increase in the basal release of glutamate . Magnesium deficit may be involved in such an age-related increase in extracellular concentration of glutamate since magnesium is well known to reduce spontaneous transmitter release presynaptically [114-117]. Accordingly, experiments carried out at neuromuscular junctions indicate that spontaneous miniature end-plate potentials increase in amplitude during ageing due to an impaired regulation of transmitter release by magnesium . Glutamate-dependent synaptic transmission is mediated by both ionotropic and metabotropic receptors [119, 120]. Fast glutamatergic synaptic responses mediated by a-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) and kainate subtypes of ionotropic receptors as well as long-lasting potentials dependent on the activation of N-methylD-aspartate (NMDA) receptors are significantly depressed in the hippocampus during the course of ageing [65, 121-129]. Mechanisms of impaired glutamatergic neurotransmission, which correlate with memory deficits (for reviews see [46, 47]), are region-specific within the hippocampus and include a loss of functional synaptic contacts [65, 121, 129] and/or a weaker receptor density on postsynaptic cells [130-133]. Pharmacological properties of AMPA/kainate receptors of hippocampal pyramidal neurons are not sensitive to magnesium and raising the external
concentration of the cation does not affect evokedAMPA receptor-mediated excitatory postsynaptic potentials neither in young nor in aged animals [104, 105, 128]. By contrast, magnesium tightly regulates NMDA receptor activation and elevating magnesium to calcium ratio depresses NMDA receptor-mediated responses [134-137]. Magnesium exerts a voltagedependent block on NMDA receptor-associated channels and the strength of the blockade depends on the subunit composition of the receptor [138-140]. No change in NMDA receptor susceptibility to magnesium block occurs with ageing since the percent decrease in NMDA receptor activation is comparable in young and aged animals after increasing magnesium to calcium ratio [125, 128]. In addition to glutamate, activation of hippocampal NMDA receptors also requires the binding of a co-agonist, D-serine, at the glycine binding site . The content of D-serine dramatically decreases in the hippocampus with age [145-147] and restoring D-serine levels in hippocampal tissues of aged animals reverses the functional impairment of NMDA receptors [144, 146, 147]. Moreover, a long-term treatment with D-cycloserine alleviates the agerelated deficit in hippocampal memory tasks . The decrease in D-serine availability in hippocampal tissues during ageing is related to alterations of the synthesizing enzyme serine racemase whereas D-amino acid oxidase, which metabolizes D-serine, is not affected . Activity of serine racemase is potently stimulated by magnesium, which increases 5- to 10-fold the rate of racemization of L- to D-serine . Impairment of magnesium-induced activation of serine racemase may therefore represent another mechanism by which a magnesium deficit contributes to the age-related of NMDA receptor activation. Although glutamate-mediated synaptic transmission is enhanced in a magnesium-free condition throughout the lifespan, the increase is significantly larger in young than in aged animals (figure 1A) . If magnesium concentration is reduced in a medium supplemented with the NMDA receptor competitive antagonist D-2-amino-5-phosphonovalerate, the increase in synaptic responses is similar in both groups of animals (figure 1B). Thus, the weaker increase induced by low magnesium in hippocampal ageing does not reflect changes in the presynaptic release of glutamate but is the consequence of the weaker density of postsynaptic NMDA receptors in aged neurons [130, 131, 133]. Although the facilitation effect of low magnesium is reduced by age, it may represent a mechanism allowing magnesium deficit to counteract the age-related decrease in glutamatergic neurotransmission.
In contrast to ionotropic receptors, little is known about the impact of aging on metabotropic glutamate (mGlu) receptors. A recent study demonstrates only discrete region- and subtype-specific changes in the expression of mGlu receptors in the hippocampus with increasing age  while electrophysiological experiments indicate that activation of these receptors is not or is only poorly affected by age [79, 153]. Cholinergic afferents arising from the medial septum/diagonal band of Broca, represent the second major excitatory input to the hippocampal formation [154, 155]. Stimulation-induced release of acetylcholine induces a slow and long-lasting excitatory postsynaptic potential in neuronal networks of all hippocampal regions [75, 156-158], depending on the activation of muscarinic cholinergic receptors [159, 160]. The acetylcholine-mediated synaptic potential is depressed by age [69, 75, 157, 161, 162] due to a decrease in transmitter release from cholinergic terminals [163-166] and to an impaired responsiveness of postsynaptic muscarinic receptors [69, 75, 77, 162, 167]. However, no correlation has been found between the degree of memory deficit and changes in cholinergic synaptic activity [75, 158, 167] indicating that the involvement of acetylcholine in the age-related memory decline is not as critical as initially thought [168-170]. Besides its role in decreasing transmitter release including the release of acetylcholine [171, 172], magnesium regulates the activation of postsynaptic muscarinic receptors in a complex way: it reduces a nonselective cationic conductance activated by muscarinic agonists , it binds to the allosteric region of the receptor thus attenuating the inhibitory effects of some modulators  and finally it is required for the activation of G-proteins coupled to muscarinic receptors [175-177]. Considering this complex pattern of interactions, it is difficult to predict to what extent magnesium deficit contributes to the agerelated alterations of cholinergic neurotransmission. However, indirect evidence argues for an agedependent modulation of acetylcholine-dependent activity by magnesium: hypomagnesia reduces the effects of iontophoretically applied acetylcholine on neuronal responses  while the magnitude of reduced high-affinity binding at the muscarinic receptor in Alzheimerâ€™s disease is closely regulated by magnesium . Age-related changes in synaptic plasticity The nature of the physiological basis of learning and memory still remains an open issue for
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fEPSP slope (% of baseline)
180 160 140
120 100 80 0
Time (min) B fEPSP slope (% of baseline)
0 Mg2+ and 2-APV (80ÂľM)
180 160 140 120 100 80 0
Figure 1. Effects of a free-magnesium medium on extracellularly recorded excitatory synaptic responses recorded in CA1 area of young and aged rat hippocampal slices after electrical stimulation of glutamatergic afferents. A) Time-course of the increase in the magnitude of the glutamate-mediated field excitatory postsynaptic potential (fEPSP) recorded in young and aged rats after perfusion with a free-magnesium medium. B) Time-course of the increase in the magnitude of the glutamate-mediated fEPSP recorded in young and aged rats after perfusion with a free-magnesium medium supplemented with the NMDA receptor antagonist 2-amino-5-phosphonovalerate acid (2-APV). Note that in a free-magnesium medium, the increase in the glutamatergic synaptic response is weaker in aged rats. On the contrary, no age-related differences were found in the presence of 2-APV. These results indicate that i) the increase in presynaptic release of glutamate by low magnesium is not altered by age and ii) the weaker increase of glutamate-mediated excitatory postsynaptic potential in aged animals reflects the weaker density of NMDA receptors expressed by postsynaptic neurons. the neurobiologist. The current most popular hypothesis suggests that memory formation is related to changes in synaptic strength within neuronal networks. Initially proposed by Hebb , this postulate received the first convincing experimental support in the early-70s when long-term potentiation (LTP) of synaptic transmission was characterized in the dentate gyrus of the hippocampus [181, 182]. LTP consists of a long-lasting increase in the efficacy of synaptic transmission induced by a
brief tetanic stimulation of presynaptic afferents [183-191], that persists for days or weeks in vivo [66, 192-195]. Since its discovery, LTP has been subjected to particularly intense scrutiny (more than 7000 papers deal with this form of synaptic plasticity), which reveals how mechanisms involved are multiple, closely interconnected and subjected to a large range of modulations [196-206]. This review will consider only mechanisms that are critical for the expression of LTP.
Glutamatergic NMDA receptors play a pivotal role in an early phase of LTP lasting 1 to 3 hours [186, 198, 203, 207-211], but other effectors such as voltagegated calcium channels [212-219] or mGlu receptors [79, 220-225] may be involved, depending on the strength of the tetanic stimulation or on the hippocampal region where LTP is induced. At a longer lasting stage, LTP requires protein synthesis, which is promoted by activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) [226-229]. The tetanic-induced neuronal depolarization relieves NMDA receptors from their voltagedependent magnesium block and also activates calcium channels, both mechanisms allowing a massive calcium entry into postsynaptic neurons [230-235]. Besides, mGlu receptor activation mediates calcium release from intracellular stores [236-239]. All these activated pathways therefore increase intracellular concentration of calcium that stimulates protein kinases (PKs) such as calcium/calmodulindependent protein kinase II (CaMKII) and PKC . As a consequence, the phosphorylation of AMPA receptors present at neuronal membranes and the incorporation of new receptors in the postsynaptic apparatus are promoted, thus increasing the strength of synaptic transmission. How LTP behaves during hippocampal ageing has been intensively investigated, mostly at CA3-CA1 synapses. Opposite conclusions were reached, at least concerning the first PKA-independent phase of LTP (for reviews see [46, 47, 245]). Whereas a first set of reports indicated that LTP is impaired by age in correlation with memory deficits, a second series did not found any significant changes. This apparent controversy is explained by differences in technical protocols used to induce LTP. In the case of â€œweakâ€? conditioning stimulation, selectively activating NMDA receptors, LTP is impaired in aged animals due to the decreased density of receptors [246-249] or their weaker activation induced by D-serine deficit [144, 146, 147]. Using a stronger conditioning stimulation recruits, in addition to NMDA receptors, voltage-gated calcium channels [212, 213, 218, 219]. Because these channels are up-regulated in hippocampal tissues during ageing [93-95], they contribute much more to LTP than in adulthood [147, 250, 251]. This higher involvement of calcium channels is able to counteract the age-related impairment of NMDA receptor activation, thus preventing the deficit in LTP. A role for mGlu receptors in changes of LTP during ageing remains a question largely neglected until now. Only one study shows that mGlu selective LTP, induced in hippocampal slices after blockade of
NMDA receptors and voltage-gated calcium channels, is not affected by increasing age . Finally, concerning PKA-dependent LTP, age-related defects in spatial memory are correlated with its alteration and both physiological and behavioural impairments are attenuated by pharmacological treatments enhancing the cAMP signaling pathway . Magnesium may interfere with LTP induction and/or maintenance at different levels. Indeed, treatments that lower the depolarization-induced influx of calcium into postsynaptic elements such as raising the concentration of external magnesium, selectively antagonize LTP [230-234]. Interestingly, the complete removal of magnesium in the external medium also elicits a persistent suppression of LTP in hippocampal slices [253, 254]. This unexpected inhibitory effect of magnesium-free medium is not due to changes affecting NMDA receptor properties but rather to activation signaling cascades in postsynaptic neurons that still remain to be characterized . Magnesium may also modulate calcium-activated protein kinases governing LTP. On the one hand, magnesium is able to control the subcellular localization of PKC, which closely determines the function of the protein . Through this mechanism, magnesium acts as a potent neuroprotective agent against damage to glutamatergic synaptic transmission induced by cerebral anoxia . On the other hand, the long-lasting potentiation of synaptic potentials induced by a magnesium-free treatment in cultured chick cerebral neurons is mediated by activation of PKC and CaMKII but not of PKA . Finally, the dephosphorylation and deactivation of CaMKII in betaTC3-cells are stimulated by magnesium . Taken together, these data raise the possibility that the early phases of LTP, which are closely dependent on PKC and CaMKII activation, may be sensitive to changes in magnesium environment whereas the PKA-mediated longer lasting stage may be much less influenced. This hypothesis has received its first experimental support since raising magnesium levels in hippocampal slices depresses LTP magnitude [230, 260]. The magnitude of short-lasting synaptic potentiation is decreased by magnesium in a similar way in hippocampal slices from both young and aged animals . Although such experiments need to be replicated, they suggest that magnesium deficiency associated with ageing does not significantly interfere with the deficit of synaptic potentiation, at least when only NMDA receptors are concerned. However, the possibility that magnesium deficiency contributes to the higher expression of voltage-gated
AGEING, HIPPOCAMPAL SYNAPTIC ACTIVITY AND MAGNESIUM
calcium channels in LTP processes during ageing remains an open issue. A role has been attributed to magnesium in the age-related alteration of another form of synaptic plasticity, namely long-term depression (LTD) of synaptic transmission. In striking contrast to LTP which requires a transient but massive calcium entry into postsynaptic cells, LTD is induced by a low frequency but prolonged conditioning stimulation producing a moderate and progressive increase in calcium concentration [261, 262]. This pattern of activation recruits protein phosphatases (PP) and particularly PP1 and PP2B (calcineurin) which promote the dephosphorylation or the internalization of AMPA receptors present at postsynaptic mem-
branes, thus decreasing the strength of synaptic transmission [263-266]. Several forms of LTD coexist in the hippocampus, which involve activation of NMDA receptors, mGlu receptors or phospholipase C, depending on the sub-region considered or on the type of conditioning stimulation [263, 267-270]. As previously described for LTP, whether NMDA receptor-mediated LTD displays an increased [271, 272] or a decreased [273, 274] susceptibility with age remains controversial. Because the calcium/ magnesium ratio determines the occurrence of LTD, a possible explanation may arise from differences in synaptic magnesium availability. A calcium/ magnesium ratio close to 1 does not induce LTD in adulthood [261, 262, 275, 276] whereas a sustained
Ca2+ L-serine VGCC
Serine racemase Mg
Figure 2. Schematic representation of the mechanisms allowing magnesium to modulate functional properties of hippocampal networks. Age-related magnesium deficit may therefore impair hippocampal functioning through several mechanisms involving presynaptic terminals, postsynaptic neurons and astrocyte glial cells. AMPAr: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, DAAOx: D-amino acid oxidase, NMDAr: N-methyl-D-aspartate receptor, VGCC: voltage-gated calcium channels.
depression is found in ageing [271, 277, 278]. This age-related facilitation of LTD processes is prevented by calcium channel antagonists , but also after raising magnesium levels  indicating that it is due to the up-regulation of voltage-gated calcium channels. On the other hand, a calcium/magnesium ratio exceeding 1.5 already induces a LTD strong enough to minimize a possible facilitation by voltage-gated calcium channels in young animals. Indeed in these conditions, LTD is not enhanced but decreased in aged animals due to the weaker activation of NMDA receptors [273, 274]. The status of the different divalent cations, and particularly of magnesium, at the synaptic cleft appears therefore essential to predict whether LTD processes will be favoured or not during ageing. This regulatory mechanism is of particular importance since LTD also determines the efficacy of learning and memory by limiting acquisition and favouring memory declines [279, 280]. Alternatively, competitive interactions between LTD and LTP in the hippocampus underlie the storage of emotional memories and stress-induced amnesia [281, 282]. Therefore, there is no doubt that an alteration in the balance between these forms of synaptic plasticity due to changes in magnesium status may significantly contribute to the memory defect of the elderly. Conclusion Reviewing forty years of research dedicated to brain ageing clearly indicates that most of the functional properties of neuronal networks within the CNS are affected by age. Considering the hippocampal formation, evidence is now provided that cellular mechanisms involved in memory formation, such as AHP or long-lasting synaptic plasticity, are significantly affected with advancing age in parallel to the impairment of cognitive performances. Although there remains a long way to go, experimental data progressively accumulate indicating that a magnesium deficit is a relevant factor for ageing-associated susceptibility to hippocampus decline, not only through a vicious circle involving magnesium, stress and hyperglucocorticism as previously suggested, [61, 283] but also by directly acting on cellular properties of hippocampal networks (figure 2).
References 1. The sex and age distribution of the world population: sex and age. Sales: United Nations publication, 1998; (vol II: E99XIII8). 2. Craik FIM. The handbook of aging and cognition. New Jersey: Lawrence Erlbaum Associates, 1992. 3. Crook T, Bartus RT, Ferris SH, Whitehouse P, Cohen GD, Gershon S. Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change. Report of a National Institute of Mental Health Work Group. Dev Neuropsychol 1986; 2: 261-76. 4. Sobow T, Flirski M, Liberski PP. Amyloid-beta and tau proteins as biochemical markers of Alzheimer’s disease. Acta Neurobiol Exp (Warsz) 2004; 64: 53-70. 5. Hampel H, Goernitz A, Buerger K. Advances in the development of biomarkers for Alzheimer’s disease: from CSF total tau and Abeta(1-42) proteins to phosphorylated tau protein. Brain Res Bull 2003; 61: 243-53. 6. Driscoll I, Sutherland RJ. The aging hippocampus: navigating between rat and human experiments. Rev Neurosci 2005; 16: 87-121. 7. Ottinger MA, Abdelnabi M, Li Q, Chen K, Thompson N, Harada N, Viglietti-Panzica C, Panzica GC. The Japanese quail: a model for studying reproductive aging of hypothalamic systems. Exp Gerontol 2004; 39: 1679-93. 8. Butterfield DA, Poon HF. The senescence-accelerated prone mouse (SAMP8): A model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer’s disease. Exp Gerontol 2005; 40: 774-83. 9. Melov S, Coskun PE, Wallace DC. Mouse models of mitochondrial disease, oxidative stress, and senescence. Mutat Res 1999; 434: 233-42. 10. Jucker M, Ingram DK. Murine models of brain aging and age-related neurodegenerative diseases. Behav Brain Res 1997; 85: 1-26. 11. Gallagher M, Rapp PR. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol 1997; 48: 339-70. 12. Woodruff-Pak DS, Trojanowski JQ. The older rabbit as an animal model: implications for Alzheimer’s disease. Neurobiol Aging 1996; 17: 283-90. 13. Cummings BJ, Head E, Ruehl W, Milgram NW, Cotman CW. The canine as an animal model of human aging and dementia. Neurobiol Aging 1996; 17: 259-68. 14. Price DL, Martin LJ, Sisodia SS, Wagster MV, Koo EH, Walker LC, Koliatsos VE, Cork LC. Aged non-human primates: an animal model of age-associated neurodegenerative disease. Brain Pathol 1991; 1: 287-96.
15. Barnes CA. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 1979; 93: 74-104.
The author is grateful to Drs A. Jouvenceau and J. Epelbaum for critical evaluation and generous assistance in correcting the manuscript.
16. Ruthrich HL, Wetzel W, Matthies H. Memory retention in old rats: improvement by orotic acid. Psychopharmacology (Berl) 1983; 79: 348-51.
AGEING, HIPPOCAMPAL SYNAPTIC ACTIVITY AND MAGNESIUM
17. Gallagher M, Pelleymounter MA. Spatial learning deficits in old rats: a model for memory decline in the aged. Neurobiol Aging 1988; 9: 549-56.
33. Winocur G. The effects of retroactive and proactive interference on learning and memory in old and young rats. Dev Psychobiol 1984; 17: 537-45.
18. Soffie M, Lejeune H. Acquisition and long-term retention of a two-level DRL schedule: comparison between mature and aged rats. Neurobiol Aging 1991; 12: 25-30.
34. Marighetto A, Etchamendy N, Touzani K, Torrea CC, Yee BK, Rawlins JN, Jaffard R. Knowing which and knowing what: a potential mouse model for age-related human declarative memory decline. Eur J Neurosci 1999; 11: 3312-22.
19. Lanahan A, Lyford G, Stevenson GS, Worley PF, Barnes CA. Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats. J Neurosci 1997; 17: 2876-85. 20. Norris CM, Foster TC. MK-801 improves retention in aged rats: implications for altered neural plasticity in age-related memory deficits. Neurobiol Learn Mem 1999; 71: 194-206. 21. Ward MT, Oler JA, Markus EJ. Hippocampal dysfunction during aging I: deficits in memory consolidation. Neurobiol Aging 1999; 20: 363-72. 22. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA 2003; 100: 14385-90. 23. Salinas JA, Gold PE. Glucose regulation of memory for reward reduction in young and aged rats. Neurobiol Aging 2005; 26: 45-52. 24. Turner E. Hippocampus and memory. Lancet 1969; 2: 1123-6. 25. Zornetzer SF, Chronister RB. Neuroanatomical localization of memory disruption: relationship between brain structure and learning task. Physiol Behav 1973; 10: 747-50. 26. Wallace RB, Kaplan R, Werboff J. Hippocampus and behavioral maturation. Int J Neurosci 1977; 7: 185-200. 27. Aggleton JP, Hunt PR, Rawlins JN. The effects of hippocampal lesions upon spatial and non-spatial tests of working memory. Behav Brain Res 1986; 19: 133-46.
35. Stoelzel CR, Stavnezer AJ, Denenberg VH, Ward M, Markus EJ. The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze. Neurobiol Learn Mem 2002; 78: 217-33. 36. Winocur G. Conditional learning in aged rats: evidence of hippocampal and prefrontal cortex impairment. Neurobiol Aging 1992; 13: 131-5. 37. Teyler TJ, Discenna P. Long-term potentiation as a candidate mnemonic device. Brain Res 1984; 319: 15-28. 38. Martin SJ, Grimwood PD, Morris RG. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 2000; 23: 649-711. 39. Gerlai R. Hippocampal LTP and memory in mouse strains: is there evidence for a causal relationship? Hippocampus 2002; 12: 657-66. 40. Lynch MA. Long-term potentiation and memory. Physiol Rev 2004; 84: 87-136. 41. Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulus of perforant path. J Physiol 1973; 232: 331-56. 42. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31-9. 43. Bear MF, Malenka RC. Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 1994; 4: 389-99. 44. Larkman AU, Jack JJ. Synaptic plasticity: hippocampal LTP. Curr Opin Neurobiol 1995; 5: 324-34.
28. Grabowska A, Luczywek E, Fersten E, Herman A, Szatkowska I. Memory impairment in patients with stereotaxic lesions to the hippocampus and amygdala. Acta Neurobiol Exp (Warsz) 1994; 54: 393-403.
45. Driscoll I, Hamilton DA, Petropoulos H, Yeo RA, Brooks WM, Baumgartner RN, Sutherland RJ. The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex 2003; 13: 1344-51.
29. Alvarez P, Zola-Morgan S, Squire LR. Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys. J Neurosci 1995; 15: 3796-807.
46. Rosenzweig ES, Barnes CA. Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog Neurobiol 2003; 69: 143-79.
30. Mumby DG, Astur RS, Weisend MP, Sutherland RJ. Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations. Behav Brain Res 1999; 106: 97-107.
47. Foster TC. Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res Rev 1999; 30: 236-49.
31. Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H. Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 2002; 9: 49-57. 32. Hampton RR, Hampstead BM, Murray EA. Selective hippocampal damage in rhesus monkeys impairs spatial memory in an open-field test. Hippocampus 2004; 14: 808-18.
48. Wu WW, Oh MM, Disterhoft JF. Age-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory. Ageing Res Rev 2002; 1: 181-207. 49. Nichols NR, Zieba M, Bye N. Do glucocorticoids contribute to brain aging? Brain Res Rev 2001; 37: 273-86. 50. Lynch MA. Analysis of the mechanisms underlying the age-related impairment in long-term potentiation in the rat. Rev Neurosci 1998; 9: 169-201.
51. Roberts Jr. EL. Using hippocampal slices to study how aging alters ion regulation in brain tissue. Methods 1999; 18: 150-9.
68. Barnes CA. Memory deficits associated with senescence: a neurophysiological and behavioural study in the rat. J Comp Physiol Psychol 1979; 93: 74-104.
52. Khachaturian ZS. Towards theories of brain aging. In: Kay D, Burrows GD, eds. Handbook of studies in psychiatry and old age. Amsterdam: Elsevier, 1984: 7-30.
69. Segal M. Changes in neurotransmitter actions in the aged rat hippocampus. Neurobiol Aging 1982; 3: 121-4.
53. Kanowski S. Aging, dementia and calcium metabolism. J Neural Transm Suppl 1998; 54: 195-200. 54. Gibson GE, Peterson C. Calcium and the aging nervous system. Neurobiol Aging 1998; 8: 329-43. 55. Verkhratsky A, Toescu EC. Calcium and neuronal ageing. Trends Neurosci 1998; 21: 2-7. 56. Landfield PW, Pitler TA. Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 1984; 226: 1089-92. 57. Xiong J, Verkhratsky A, Toescu EC. Changes in mitochondrial status associated with altered Ca2+ homeostasis in aged cerebellar granule neurons in brain slices. J Neurosci 2002; 22: 10761-71. 58. Disterhoft JF, Wu WW, Ohno M. Biophysical alterations of hippocampal pyramidal neurons in learning, ageing and Alzheimerâ€™s disease. Ageing Res Rev 2004; 3: 383406. 59. Toescu EC, Verkhratsky A, Landfield PW. Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci 2004; 27: 614-20. 60. Poenaru S, Manicom R, Rouhani S, Aymard P, Bajenaru O, Rayssiguier Y, Emmanouillidis E, Gueux E, Nkanga N, Durlach J, Dallâ€™ava J. Stability of brain content of magnesium in experimental hypomagnesemia. Brain Res 1997; 769: 329-32. 61. Durlach J, Bac P, Durlach V, Rayssiguier Y, Bara M, Guiet-Bara A. Magnesium status and ageing: An update. Magnes Res 1998; 11: 25-42. 62. Standley CA, Cotton DB. Brain ionised magnesium and calcium levels during magnesium supplementation and deficiency in female Long-Evans rats. Obstet Gynecol 1996; 88: 184-8. 63. Andrasi E, Pali N, Molnar Z, Kosel S. Brain aluminium, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimer Dis 2005; 7: 273-84. 64. Bardgett ME, Schultheis PJ, McGill DL, Richmond RE, Wagge JR. Magnesium deficiency impairs fear conditioning in mice. Brain Res 2005; 1038: 100-6. 65. Barnes CA, McNaughton BL. Physiological compensation for loss of afferent synapses in rat granule cells during senescence. J Physiol 1980; 309: 473-85. 66. Barnes CA, Suster MS, Shen J, McNaughton BL. Multistability of cognitive maps in the hippocampus of old rats. Nature 1997; 388: 272-5. 67. Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci 2005; 25: 6877-86.
70. Landfield PW, Pitler TA. Prolonged Ca2+-dependent after-hyperpolarizations in hippocampal neurons of aged rats. Science 1984; 226: 1089-92. 71. Niesen CE, Baskys A, Carlen PL. Reversed ethanol effects on potassium conductances in aged hippocampal dentate granule neurons. Brain Res 1988; 445: 13741. 72. Kerr DS, Campbell LW, Hao SY, Landfield PW. Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science 1989; 245: 1505-9. 73. Pitler TA, Landfield PW. Aging-related prolongation of calcium spike duration in rat hippocampal slice neurons. Brain Res 1990; 508: 1-6. 74. Turner DA, Deupree DL. Functional elongation of CA1 hippocampal neurons with aging in Fischer 344 rats. Neurobiol Aging 1991; 12: 201-10. 75. Potier B, Rascol O, Jazat F, Lamour Y, Dutar P. Alterations in the properties of hippocampal pyramidal neurons in the aged rat. Neuroscience 1992; 48: 793-806. 76. Moyer Jr. JR, Thomson LT, Black JP, Disterhoft JF. Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age- and concentration-dependent manner. J Neurophysiol 1992; 68: 2100-9. 77. Potier B, Lamour Y, Dutar P. Age-related alterations in the properties of hippocampal pyramidal neurons among rat strains. Neurobiol Aging 1993; 14: 17-25. 78. Billard JM, Lamour Y, Dutar P. Decreased monosynaptic GABAB-mediated postsynaptic potentials in hippocampal CA1 pyramidal cells in the aged rat: Pharmacological characterization and possible mechanisms. J Neurophysiol 1995; 74: 539-46. 79. Jouvenceau A, Dutar P, Billard JM. Is activation of the metabotropic glutamate receptors impaired in the hippocampal CA1 area of the aged rat. Hippocampus 1997; 7: 455-9. 80. Billard JM, Jouvenceau A, Lamour Y, Dutar P. NMDA receptor activation in the aged rat: electrophysiological investigations in the CA1 area of the hippocampal slice ex vivo. Neurobiol Aging 1997; 8: 535-42. 81. Thibaut O, Hadley R, Landfield PW. Elevated postsynaptic [Ca2+]I and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci 2001; 21: 9744-56. 82. Power JM, Wu WW, Sametsky E, Oh MM, Disterhoft JF. Age-related enhancement of the slow-outward calciumactivated potassium current in hippocampal CA1 pyramidal neurons in vitro. J Neurosci 2002; 22: 7234-43. 83. Hsu KS, Huang CC, Liang YC, Wu HM, Chen YL, Lo SW, Ho WC. Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation. Hippocampus 2002; 12: 787-802.
AGEING, HIPPOCAMPAL SYNAPTIC ACTIVITY AND MAGNESIUM
84. Chung YH, Joo KM, Kim MJ, Cha CL. Age-related changes in the distribution of Na(v)11 and Na(v)12 in rat cerebellum. Neuroreport 2003; 14: 841-5.
tates trace eyeblick conditioning in aging rabbits and increases the excitability of CA1 pyramidal neurons. J Neurosci 2000; 20: 783-90.
85. Hotson JR, Prince DA. A calcium-activated hyperpolarization follows repetitive firing in hippocampal neurons. J Neurophysiol 1980; 43: 409-19.
100. Anderson P, Lomo T. Control of hippocampal output by afferent volley frequency. In: Adey WR, Tokizane T, eds. Structure and function of the limbic system. Progress in Brain Res. Amsterdam: Elsevier, 1967: 400-13; (27).
86. Madison D, Nicoll RA. Control of the repetitive discharge of rat CA1 pyramidal neurons in vitro. J Physiol 1984; 354: 319-31. 87. Storm J, Hvalby O. Repetitive firing of CA1 hippocampal pyramidal cells elicited by dendritic glutamate: slow prepotentials and burst-pause pattern. Exp Brain Res 1985; 60: 10-8. 88. Lorenzon NM, Foehring RC. Relationship between repetitive firing and afterhyperpolarizations in human neocortical neurons. J Neurophysiol 1992; 67: 350-63. 89. Moyer Jr. JR, Thomson LT, Disterhoft JF. Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner. J Neurosci 1996; 16: 553646.
101. Thibault O, Hadley R, Landfield PW. Elevated postsynaptic (Ca2+)i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci 2001; 21: 9744-56. 102. Landfield PW, Lynch GL. Impaired monosynaptic potentiation in vitro hippocampal slices from aged, memory-deficient rats. J Gerontol 1977; 32: 523-33. 103. Diana G, Scotti De Carolis A, Frank C, Domenici MR, Sagratella S. Selective reduction of hippocampal dentate frequency potentiation in aged rats with impaired place learning. Brain Res Bull 1994; 35: 107-11.
90. Thomson LT, Moyer Jr. JR, Disterhoft JF. Transient changes in excitability of rabbit CA3 neurons with a time-course appropriate to support memory consolidation. J Neurophysiol 1996; 76: 1836-49.
104. Landfield PW, Morgan GA. Chronically elevating plasma Mg2+ improves hippocampal frequency potentiation and reversal learning in aged and young rats. Brain Res 1984; 322: 167-71.
91. Oh MM, Kuo AG, Wu WW, Sametsky EA. Watermaze learning enhances excitability of CA1 pyramidal neurons. J Neurophysiol 2003; 90: 2171-9.
105. Landfield PW, Pitler TA, Applegate MD. The effects of high Mg2+-to-Ca2+ ratios on frequency potentiation in hippocampal slices of young and aged rats. J Neurophysiol 1986; 56: 797-811.
92. Tombaugh GC, Rowe WB, Rose GM. The slow afterhyperpolarization in hippocampal CA1 neurons covaries with spatial learning ability in aged Fisher 344 rats. J Neurosci 2005; 25: 2609-16. 93. Thibault O, Landfield PW. Increase in single L-type calcium channels in hippocampal neurons during aging. Science 1996; 272: 1017-20. 94. Davare MA, Hell JW. Increased phosphorylation of the neuronal L-type Ca(2+) channel Ca(v)12 during aging. Proc Natl Acad Sci USA 2003; 100: 16018-23. 95. Campbell LW, Hao SY, Thibault O, Blalock EM, Landfield PW. Aging changes in voltage-gated calcium currents in hippocampal CA1 neurons. J Neurosci 1996; 16: 6286-95. 96. Moyer JR, Power JM, Thomson LT, Disterhoft JF. Increased excitability of aged rabbit CA1 neurons after trace eyeblink conditioning. J Neurosci 2000; 20: 547682. 97. Veng LM, Mesches MH, Browning MD. Age-related working memory impairment is correlated with increases in the L-type calcium channel protein alpha1D (Cav13) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment. Brain Res Mol Brain Res 2003; 110: 193-202. 98. Oh MM, Power JM, Thompson LT, Moriearty PL, Disterhoft JF. Metrifonate increases neuronal excitability in CA1 pyramidal neurons from both young and aging rabbit hippocampus. J Neurosci 1999; 19: 1814-23. 99. Weiss C, Preston AR, Oh MM, Schwartz RD, Welty D, Disterhoft JF. The M1 muscarinic agonist CI-1017 facili-
106. Johnson JL. Glutamic acid as a synaptic transmitter in the nervous system A review. Brain Res 1972; 37: 1-19. 107. Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J Neurochem 1984; 42: 1-11. 108. Fagg GE, Foster AC. Amino acid neurotransmitters and their pathways in the mammalian central nervous system. Neuroscience 1983; 9: 701-19. 109. Di Lauro A, Schmid RW, Meek JL. Is aspartic acid the neurotransmitter of the perforant pathway? Brain Res 1981; 207: 476-80. 110. Collingridge GL, Kehl SJ, McLennan H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol 1983; 334: 33-46. 111. Fleck MW, Henze DA, Barrionuevo G, Palmer AM. Aspartate and glutamate mediate excitatory synaptic transmission in area CA1 of the hippocampus. J Neurosci 1993; 13: 3944-55. 112. Segovia G, Porras A, Del Arco A, Mora F. Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev 2001; 122: 1-29. 113. Massieu L, Tapia R. Glutamate uptake impairment and neuronal damage in young and aged rats in vivo. J Neurochem 1997; 69: 1151-60. 114. Hubbard JL. The effect of calcium and magnesium on the spontaneous release of transmitter from mammalian motor nerve endings. J Physiol 1961; 159: 507-17.
115. Okada K. Effect of calcium and magnesium on spontaneous transmitter release accelerated by raised potassium. Brain Res 1973; 53: 237-42. 116. Muller RU, Finkelstein A. The electrostatic basis of Mg2+ inhibition of transmitter release. Proc Natl Acad Sci USA 1974; 71: 923-6. 117. Kuno M, Takahashi T. Effects of calcium and magnesium on transmitter release at Ia synapses of rat spinal motoneurons in vitro. J Physiol 1986; 376: 543-53. 118. Kelly SS, Robbins N. Progression of age in synaptic transmission at mouse neuromuscular junctions. J Physiol 1983; 343: 375-83. 119. Monaghan DT, Bridges RJ, Cotman CW. The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharm Toxicol 1989; 29: 365402. 120. Hollmann D, Heinemenn S. Cloned glutamate receptors. Annu Rev Neurosci 1994; 17: 31-108. 121. Barnes CA, Rao G, Foster TC, McNaughton B. Regionspecific age effects on AMPA sensitivity: electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1. Hippocampus 1992; 2: 457-68. 122. Bauman LA, Mahle CD, Boissard CG, Gribkoff VK. Age-dependence of effects of A1 adenosine receptor antagonism in rat hippocampal slices. J Neurophysiol 1992; 68: 629-38. 123. Deupree DL, Bradley J, Turner DA. Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol Aging 1993; 14: 249-58. 124. Papatheodroropoulos C, Kostopoulos G. Age-related changes in excitability and recurrent inhibition in the rat CA1 hippocampal region. Eur J Neurosci 1996; 8: 510-20. 125. Barnes CA, Rao G, Shen J. Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1. Neurobiol Aging 1997; 18: 445-52. 126. Jouvenceau A, Dutar P, Billard JM. Alteration of NMDA receptor-mediated synaptic responses in CA1 area of the aged rat hippocampus: contribution of GABAergic and cholinergic deficits. Hippocampus 1998; 8: 627-37. 127. Barnes CA, Rao G, Orr G. Age-related decrease in the Schaeffer collateral-evoked EPSP in awake, freely behaving rats. Neural Plast 2000; 7: 167-78. 128. Potier B, Poindessous-Jazat F, Dutar P, Billard JM. NMDA receptor activation in the aged rat hippocampus. Exp Gerontol 2000; 35: 1185-99. 129. Barnes CA, Rao G, Houston FP. LTP induction threshold change in old rats at the perforant path-granule cell synapse. Neurobiol Aging 2000; 21: 613-20. 130. Magnusson KR. Declines in mRNA expression of different subunits may account for differential effects of aging on agonist and antagonist binding to the NMDA receptor. J Neurosci 2000; 20: 1666-74.
131. Clark AS, Magnusson KR, Cotman CW. In vitro autoradiography of hippocampal excitatory amino acid binding in aged Fischer 344 rats: relationship to performance on the Morris water maze. Behav Neurosci 1999; 106: 324-35. 132. Pagliusi SR, Gerrard P, Abdallah M, Talabot D, Catsicas S. Age-related changes in expression of AMPA-selective glutamate receptor subunits: is calcium-permeability altered in hippocampal neurons? Neuroscience 1994; 61: 429-33. 133. Wenk GL, Barnes CA. Regional changes in the hippocampal density of AMPA and NMDA receptors across the lifespan of the rat. Brain Res 2000; 885: 1-5. 134. Mayer ML, Westbrook GL, Guthrie PB. Voltagedependence blockade by Mg2+ of NMDA responses in spinal cord neurons. Nature 1984; 309: 261-3. 135. Nowak L, Bregestowski P, Ascher P, Herbert A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurons. Nature 1984; 307: 462-5. 136. Li-Smerin Y, Johnson JW. Kinetics of the block by intracellular Mg2+ of the NMDA-activated channel in cultured rat neurons. J Physiol 1996; 491: 121-35. 137. Li-Smerin Y, Johnson JW. Effects of intracellular Mg2+ on channel gating and steady-state response of the NMDA receptor in cultured rat neurons. J Physiol 1996; 491: 137-50. 138. Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M, Mishina M. Molecular diversity of the NMDA receptor channel. Nature 1992; 358: 36-41. 139. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH. Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 1992; 256: 1217-20. 140. Qian A, Buller AL, Johnson JW. NR2 subunitdependence of NMDA receptor block by external Mg2+. J Physiol 2005; 562: 319-31. 141. Potier B, Jouvenceau A, Poindessous-Jazat F, Dutar P, Billard JM. Modulation of the NMDA receptor by magnesium: comparison in young and aged rats. Soc Neurosc Abst 1999; 25: 68220. 142. Mothet JP, Parent AT, Wolosker H, Brady Jr. RO, Linden DJ, Ferris CD, Rogawski MA, Snyder SH. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 2000; 97: 4926-31. 143. Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci USA 2003; 100: 15194-9. 144. Yang S, Qiao H, Wen L, Zhou WW, Zhang Y. D-serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescenceaccelerated mouse prone/8. Neurosci Lett 2005; 379: 7-12.
AGEING, HIPPOCAMPAL SYNAPTIC ACTIVITY AND MAGNESIUM
145. Williams SM, Diaz CM, MacNab LT, Sullivan RK, Pow D. Immunocytochemical analysis of D-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons. Glia 2006; 53: 401-11. 146. Mothet JP, Rouaud E, Sinet PM, Potier B, Jouvenceau A, Dutar P, Videau C, Epelbaum J, Billard JM. A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory. Aging Cell 2006; 5: 267-74. 147. Junjaud G, Rouaud E, Turpin F, Mothet JP, Billard JM. Age-related effects of the glio-neuromodulator D-serine on neurotransmission and synaptic potentiation in the CA1 hippocampal area of the rat. J Neurochem 2006; (in press). 148. Baxter MG, Lanthorn TH, Frick KM, Golski S, Wan RQ, Olton DS. D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats. Neurobiol Aging 1994; 15: 207-13. 149. Aura J, Riekkinen Jr. P. Pre-training blocks the improving effect of tetrahydroaminoacridine and D-cycloserine on spatial navigation performance in aged rats. Eur J Pharmacol 2000; 390: 313-8. 150. Thompson LT, Disterhoft JF. Age- and dose-dependent facilitation of associative eyeblink conditioning by D-cycloserine in rabbits. Behav Neurosci 1997; 111: 1303-12. 151. De Miranda J, Panizzutti R, Foltyn VN, Wolosker H. Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. Proc Natl Acad Sci USA 2002; 99: 14542-7. 152. Simonyi A, Ngomba RT, Storto M, Catania MV, Miller LA, Youngs B, DiGiorgi-Gerevini V, Nicoletti F, Sun GY. Expression of groups I and II metabotropic glutamate receptors in the rat brain during aging. Brain Res 2005; 1043: 95-106. 153. Nicolle MM, Colombo PJ, Gallagher M, McKinney M. Metabotropic glutamate receptor-mediated hippocampal phosphoinositide turnover is blunted in spatial learning-impaired aged rats. J Neurosci 1999; 19: 960410. 154. Mesulam MM, Mufson EJ, Wainer BH, Levet AI. Central cholinergic pathways in the rat: overview based on an alternative nomenclature (ch1-ch6). Neuroscience 1983; 10: 1185-201.
158. Shen J, Barnes CA. Age-related decrease in cholinergic synaptic transmission in three hippocampal subfields. Neurobiol Aging 1996; 17: 439-51. 159. Dutar P, Nicoll RA. Classification of muscarinic responses in hippocampus in terms of receptor subtypes and second-messenger systems: electrophysiological studies in vitro. J Neurosci 1988; 8: 4214-24. 160. Muller W, Misgeld U. Slow cholinergic excitation of guinea pig hippocampal neurons is mediated by two muscarinic receptor subtypes. Neurosci Lett 1986; 102: 107-12. 161. Taylor L, Griffith WH. Age-related decline in cholinergic synaptic transmission in hippocampus. Neurobiol Aging 1993; 14: 509-15. 162. Lippa AS, Loullis CC, Rotrosen J, Cordasco DM, Critchett DJ. Conformational changes in muscarinic receptors may produce diminished cholinergic neurotransmission and memory deficits in aged rats. Neurobiol Aging 1985; 6: 317-23. 163. Takei N, Nihonmatsu I, Kawamura H. Age-related decline of acetylcholine release evoked by depolarizing stimulation. Neurosci Lett 1989; 101: 182-6. 164. Scali C, Casamenti F, Pazzagli M, Bartolini L, Pepeu G. Nerve growth factor increases extracellular acetylcholine levels in the parietal cortex and hippocampus of aged rats and restores object recognition. Neurosci Lett 1994; 170: 117-20. 165. Aubert I, Rowe W, Meaney MJ, Gauthier S, Quirion R. Cholinergic markers in aged cognitively impaired Long-Evans rats. Neuroscience 1995; 67: 277-92. 166. Birthelmer A, Stemmelin J, Jackisch R, Cassel JC. Presynaptic modulation of acetylcholine, noradrenaline, and serotonin release in the hippocampus of aged rats with various levels of memory impairments. Brain Res Bull 2003; 60: 283-96. 167. Calhoun ME, Mao Y, Roberts JA, Rapp PR. Reduction in hippocampal cholinergic innervation is unrelated to recognition memory impairment in aged rhesus monkeys. J Comp Neurol 2004; 475: 238-426. 168. Bartus RT, Dean 3rd RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 408-14. 169. Pepeu G. Acetylcholine and brain aging. Pharmacol Res Commun 1988; 20: 91-7. 170. Bartus RT. On neurodegenerative diseases, models, and treatment strategies: Lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 2000; 163: 495-529.
155. Krnjevic K, Ropert N. Septo-hippocampal pathway modulates hippocampal activity by a cholinergic mechanism. Can J Physiol Pharmacol 1981; 59: 911-4.
171. Jope RS. Acetylcholine turnover and compartmentation in rat brain synaptosomes. J Neurochem 1981; 36: 1712-21.
156. Cole AE, Nicoll RA. Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells. Science 1983; 221: 1299-301.
172. Vicroy TW, Schneider CJ. Characterization of divalent cation-induced [3H] acetylcholine release from EGTAtreated rat hippocampal synaptosomes. J Neurochem 1991; 16: 1175-85.
157. Madison DV, Lancaster B, Nicoll RA. Voltage clamp analysis of cholinergic action in the hippocampus. J Neurosci 1987; 7: 733-41.
173. Guerineau NC, Bossu JL, Gahwiler BH, Gerber U. Activation of a nonselective cationic conductance by
metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus. J Neurosci 1995; 15: 4395-407. 174. Burgmer U, Schulz U, Trankle C, Mohr K. Interaction of Mg2+ with the allosteric site of muscarinic M2 receptors. Naunyn Schmiedebergs Arch Pharmacol 1998; 357: 363-70. 175. Shiozaki K, Haga T. Effects of magnesium ion on the interaction of atrial muscarinic acetylcholine receptors and GTP-binding regulatory proteins. Biochemistry 1992; 31: 10634-42. 176. Cladman W, Chidiac P. Characterization and comparison of RGS2 and RGS4 as GTPase-activating proteins for M2 muscarinic receptor-stimulated G(i). Mol Pharmacol 2002; 62: 654-9. 177. Zhang Q, Okamura M, Guo ZD, Haga T. Effects of partial agonist and Mg2+ ions on the interaction of M2 muscarinic acetylcholine receptor and G protein G alpha i1 subunit in the M2-G aapha i1 fusion protein. J Biochem (Tokyo) 2004; 135: 589-96. 178. El-Beheiry H, Puil E. Effects of hypomagnesemia on transmitter actions in neocortical slices. Br J Pharmacol 1990; 101: 1006-10. 179. Ladner CJ, Lee JM. Reduced high-affinity agonist binding at the M(1) muscarinic receptor in Alzheimerâ€™s disease brain: differential sensitivity to agonist and divalent cations. Exp Neurol 1999; 158: 451-8. 180. Hebb DO. The organization of behavior. New York: John Wiley & sons, 1949. 181. Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 1973; 232: 331-56. 182. Bliss TV, Gardner-Medwin AR. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 1973; 232: 357-74.
189. Bear MF, Malenka RC. Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 1994; 4: 389-99. 190. Martinez Jr. JL, Derrick BE. Long-term potentiation and learning. Annu Rev Psychol 1996; 47: 73-203. 191. Jeffery KJ. LTP and spatial learning. Where to next? Hippocampus 1997; 7: 95-110. 192. Douglas RM, Goddard GV. Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus. Brain Res 1975; 86: 205-15. 193. Racine RJ, Milgram NW, Hafner S. Long-term potentiation phenomena in the rat limbic forebrain. Brain Res 1983; 260: 217-31. 194. Jeffery KJ, Abraham WC, Dragunow M, Mason SE. Induction of Fos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanasthetized rats. Brain Res Mol Brain Res 1990; 8: 267-74. 195. Abraham WC, Mason-Parker SE, Williams J, Dragunow M. Analysis of the decremental nature of LTP in the dentate gyrus. Brain Res Mol Brain Res 1995; 30: 367-72. 196. Medina JH, Izquierdo I. Retrograde messengers, longterm potentiation and memory. Brain Res Rev 1995; 21: 185-94. 197. Wheal HV, Chen Y, Mitchell J, Schachner M, Maerz W, Wieland H, Van Rossum D, Kirsch J. Molecular mechanisms that underlie structural and functional changes at the postsynaptic membrane during synaptic plasticity. Prog Neurobiol 1998; 55: 611-40. 198. Sanes JR, Lichtman JW. Can molecules explain longterm potentiation? Nat Neurosci 1999; 2: 597-604. 199. Soderling TR, Derkach VA. Postsynaptic protein phosphorylation and LTP. Trends Neurosci 2000; 23: 75-80. 200. Luscher C, Nicoll RA, Malenka RC, Muller D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat Neurosci 2000; 3: 545-50.
183. Teyler TJ, Discenna P. Long-term potentiation as a candidate mnemonic device. Brain Res 1984; 319: 15-28.
201. Yuste R, Bonhoeffer T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 2001; 24: 1071-89.
184. Brown TH, Chapman PF, Kairiss EW, Keenan CL. Long-term synaptic potentiation. Science 1988; 242: 724-8.
202. Malenka RC. The long-term potential of LTP. Nat Rev Neurosci 2003; 4: 923-6.
185. Gustafsson B, Wigstrom H. Long-term potentiation in the hippocampal CA1 region: its induction and early temporal development. Prog Brain Res 1990; 83: 22332. 186. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1991; 361: 31-9. 187. Siegelbaum SA, Kandel ER. Learning-related synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 1991; 1: 113-20. 188. Baudry M, Massicotte G. Physiological and pharmacological relationships between long-term potentiation and mammalian memory. Concept Neurosci 1992; 3: 79-98.
203. Pare D. Presynaptic induction and expression of NMDA-dependent LTP. Trends Neurosci 2004; 27: 440-1. 204. Mehta MR. Cooperative LTP can map memory sequences on dendritic branches. Trends Neurosci 2004; 27: 69-72. 205. Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron 2004; 44: 5-21. 206. Lisman J, Spruston N. Postsynaptic depolarization requirements for LTP and LTD: a critique of spike timing-dependent plasticity. Nat Neurosci 2005; 8: 83941. 207. Herron CE, Lester RA, Coan EJ, Collingridge GL. Frequency-dependent involvement of NMDA recep-
AGEING, HIPPOCAMPAL SYNAPTIC ACTIVITY AND MAGNESIUM
tors in the hippocampus: a novel synaptic mechanism. Nature 1986; 322: 265-8. 208. Muller D, Joly M, Lynch G. Contributions of quisqualate and NMDA receptors to the induction and expression of LTP. Science 1988; 242: 1694-7. 209. Reymann KG, Matthies HK, Schulzeck K, Matthies H. N-methyl-D-aspartate receptor activation is required for the induction of both early and late phases of longterm potentiation in rat hippocampal slices. Neurosci Lett 1989; 96: 96-101. 210. Morris RG. Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci 1989; 9: 3040-57.
222. Aiba A, Chen C, Herrup K, Rosenmund C, Stevens CF, Tonegawa S. Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 1994; 79: 365-75. 223. Richter-Levin G, Errington ML, Maegawa H, Bliss TV. Activation of metabotropic glutamate receptors is necessary for long-term potentiation in the dentate gyrus and for spatial learning. Neuropharmacology 1994; 33: 853-7. 224. Manahan-Vaughan D, Reymann KG. Regional and developmental profile of modulation of hippocampal synaptic transmission and LTP by AP4-sensitive mGluRs in vivo. Neuropharmacology 1995; 34: 9911001.
211. Gustafsson B, Wigstrom H. Long-term potentiation in the hippocampal CA1 region: its induction and early temporal development. Prog Brain Res 1990; 83: 22332.
225. Wu J, Rush A, Rowan MJ, Anwyl R. NMDA receptorand metabotropic glutamate receptor-dependent synaptic plasticity induced by high frequency stimulation in the rat dentate gyrus in vitro. J Physiol 2001; 533: 745-55.
212. Kullmann DM, Perkel DJ, Manabe T, Nicoll RA. Ca2+ entry via postsynaptic voltage-sensitive Ca2+ channels can transiently potentiate excitatory synaptic transmission in the hippocampus. Neuron 1992; 9: 1175-83.
226. Malinow R, Madison DV, Tsien RW. Persistent protein kinase activity underlying long-term potentiation. Nature 1988; 335: 820-4.
213. Huber KM, Mauk MD, Kelly PT. Distinct LTP induction mechanisms: contribution of NMDA receptors and voltage-dependent calcium channels. J Neurophysiol 1995; 73: 270-9. 214. Wang Y, Rowan MJ, Anwyl R. LTP induction dependent on activation of Ni2+-sensitive voltage-gated calcium channels, but not NMDA receptors, in the rat dentate gyrus in vitro. J Neurophysiol 1997; 78: 2574-81. 215. Cavus I, Teyler T. Two forms of long-term potentiation in area CA1 activate different signal transduction cascades. J Neurophysiol 1996; 76: 3038-47. 216. Morgan SL, Teyler TJ. VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo. J Neurophysiol 1999; 82: 736-40. 217. Kapur A, Yeckel MF, Gray R, Johnston D. L-Type calcium channels are required for one form of hippocampal mossy fiber LTP. J Neurophysiol 1998; 79: 2181-90. 218. Borroni AM, Fichtenholtz H, Woodside BL, Teyler TJ. Role of voltage-dependent calcium channel long-term potentiation (LTP) and NMDA LTP in spatial memory. J Neurosci 2000; 20: 9272-6. 219. Freir DB, Herron CE. Inhibition of L-type voltage dependent calcium channels causes impairment of long-term potentiation in the hippocampal CA1 region in vivo. Brain Res 2003; 967: 27-36. 220. Riedel G, Wetzel W, Reymann KG. (R,S)-alpha-methyl4-carboxyphenylglycine (MCPG) blocks spatial learning in rats and long-term potentiation in the dentate gyrus in vivo. Neurosci Lett 1994; 167: 141-4. 221. Bashir ZI, Bortolotto ZA, Davies CH, Berretta N, Irving AJ, Seal AJ, Henley JM, Jane DE, Watkins JC, Collingridge GL. Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Nature 1993; 363: 347-50.
227. Frey U, Huang YY, Kandel ER. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 1993; 260: 1661-4. 228. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER. Bourtchouladze R Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampusbased long-term memory. Cell 1997; 88: 615-26. 229. Bolshakov VY, Golan H, Kandel ER, Siegelbaum SA. Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3-CA1 synapses in the hippocampus. Neuron 1997; 19: 635-51. 230. Dunwiddie TV, Lynch G. The relationship between extracellular calcium concentrations and the induction of hippocampal long-term potentiation. Brain Res 1979; 169: 103-10. 231. Malenka RC, Kauer JA, Perkel DJ, Nicoll RA. The impact of postsynaptic calcium on synaptic transmission--its role in long-term potentiation. Trends Neurosci 1989; 12: 444-50. 232. Regehr WG, Tank DW. Postsynaptic NMDA receptormediated calcium accumulation in hippocampal CA1 pyramidal cell dendrites. Nature 1990; 345: 807-10. 233. Malenka RC. The role of postsynaptic calcium in the induction of long-term potentiation. Mol Neurobiol 1991; 5: 289-95. 234. Malenka RC, Lancaster B, Zucker RS. Temporal limits on the rise in postsynaptic calcium required for the induction of long-term potentiation. Neuron 1992; 9: 121-8. 235. Perkel DJ, Petrozzino JJ, Nicoll RA, Connor JA. The role of Ca2+ entry via synaptically activated NMDA receptors in the induction of long-term potentiation. Neuron 1993; 11: 817-23. 236. Partridge LD, Valenzuela CF. Ca2+ store-dependent potentiation of Ca2+-activated non-selective cation
channels in rat hippocampal neurons in vitro. J Physiol 1999; 521: 617-27. 237. Rae MG, Irving AJ. Both mGluR1 and mGluR5 mediate Ca2+ release and inward currents in hippocampal CA1 pyramidal neurons. Neuropharmacology 2004; 46: 1057-69. 238. Fagni L, Chavis P, Ango F, Bockaert J. Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons. Trends Neurosci 2000; 23: 80-8. 239. Rae MG, Martin DJ, Collingridge GL, Irving AJ. Role of Ca2+ stores in metabotropic L-glutamate receptormediated supralinear Ca2+ signaling in rat hippocampal neurons. J Neurosci 2000; 20: 8628-36. 240. Hu GY, Hvalby O, Walaas SI, Albert KA, Skjeflo P, Andersen P, Greengard P. Protein kinase C injection into hippocampal pyramidal cells elicits features of long term potentiation. Nature 1987; 328: 426-9. 241. Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN. An essential role for postsynaptic calmodulin and protein kinase activity in longterm potentiation. Nature 1989; 340: 554-7. 242. Cheng G, Rong XW, Feng TP. Block of induction and maintenance of calcium-induced LTP by inhibition of protein kinase C in postsynaptic neuron in hippocampal CA1 region. Brain Res 1994; 646: 230-4. 243. Ben-Ari Y, Aniksztejn L, Bregestovski P. Protein kinase C modulation of NMDA currents: an important link for LTP induction. Trends Neurosci 1992; 15: 333-9. 244. Fukunaga K, Muller D, Miyamoto E. CaM kinase II in long-term potentiation. Neurochem Int 1996; 28: 34358. 245. Bergado JA, Almaguer W. Aging and synaptic plasticity: a review. Neural Plast 2002; 9: 217-32. 246. Moore CI, Browning MD, Rose GM. Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area CA1 of aged Fischer 344 rats. Hippocampus 1993; 3: 57-66. 247. Lanahan A, Lyford G, Stevenson GS, Worley PF, Barnes CA. Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats. J Neurosci 1997; 17: 2876-85. 248. Eckles-Smith K, Clayton DA, Bickford PC, Browning MD. Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression. Brain Res Mol Brain Res 2000; 78: 154-62. 249. Clayton DA, Mesches MH, Alvarez E, Bickford PC, Browning MD. A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 2002; 22: 3628-37. 250. Shankar S, Teyler TJ, Robbins N. Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J Neurophysiol 1998; 79: 334-41.
251. Izumi Y, Zorumski CF. LTP in CA1 of the adult rat hippocampus and voltage-activated calcium channels. Neuroreport 1998; 9: 3689-91. 252. Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I, Hawkins RD, Kandel ER. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci USA 1999; 96: 5280-5. 253. Frankiewicz T, Parsons CG. Memantine restores long term potentiation impaired by tonic N-methyl-Daspartate (NMDA) receptor activation following reduction of Mg2+ in hippocampal slices. Neuropharmacology 1999; 38: 1252-9. 254. Jouvenceau A, Potier B, Poindessous-Jazat F, Dutar P, Slama A, Epelbaum J, Billard JM. Decrease in calbindin content significantly alters LTP but not NMDA receptor and calcium channel properties. Neuropharmacology 2002; 42: 444-58. 255. Hsu KS, Ho WC, Huang C, Tsai JJ. Transient removal of extracellular Mg(2+) elicits persistent suppression of LTP at hippocampal CA1 synapses via PKC activation. J Neurophysiol 2000; 84: 1279-88. 256. Tanimura A, Nezu A, Morita T, Hashimoto N, Tojyo Y. Interplay between calcium, diacylglycerol, and phosphorylation in the spatial and temporal regulation of PKC alpha-GFP. J Biol Chem 2002; 277: 29054-62. 257. Libien J, Sacktor TC, Kass IS. Magnesium blocks the loss of protein kinase C, leads to a transient translocation of PKC(alpha) and PKC(esilon), and improves recovery after anoxia in rat hippocampal slices. Brain Res Mol Brain Res 2005; 136: 104-11. 258. Kudoh SN, Nagai R, Kiyosue K, Taguchi T. PKC and CaMKII dependent synaptic potentiation in cultured cerebral neurons. Brain Res 2001; 915: 79-87. 259. Easom RA, Tarpley JL, Filler NR, Bhatt H. Dephosphorylation and deactivation of Ca2+/calmodulindependent protein kinase II in betaTC3-cells is mediated by Mg2+- and okadaic-acid-sensitive protein phosphatases. Biochem J 1998; 329: 283-8. 260. Potier B, Poindessous-Jazat F, Dutar P, Billard JM. NMDA receptor activation in the aged rat. Exp Gerontol 2000; 35: 1185-99. 261. Zhuo M, Hawkins RD. Long-term depression: a learning-related type of synaptic plasticity in the mammalian central nervous system. Rev Neurosci 1995; 6: 259-77. 262. Thiels E, Xie X, Yeckel MF, Barrionuevo G, Berger TW. NMDA receptor-dependent LTD in different subfields of hippocampus in vivo and in vitro. Hippocampus 1996; 6: 43-51. 263. Mulkey RM, Herron CE, Malenka RC. An essential role for protein phosphatases in hippocampal long-term depression. Science 1993; 261: 1051-5. 264. Thiels E, Kanterewicz BI, Knapp LT, Barrionuevo G, Klann E. Protein phosphatase-mediated regulation of
AGEING, HIPPOCAMPAL SYNAPTIC ACTIVITY AND MAGNESIUM
protein kinase C during long-term depression in the adult hippocampus in vivo. J Neurosci 2000; 20: 7199207. 265. Morishita W, Connor JH, Xia H, Quinlan EM, Shenolikar S, Malenka RC. Regulation of synaptic strength by protein phosphatase 1. Neuron 2001; 32: 1133-48. 266. Isaac J. Protein phosphatase 1 and LTD: synapses are the architects of depression. Neuron 2001; 32: 963-6. 267. Manabe T. Two forms of hippocampal long-term depression, the counterpart of long-term potentiation. Rev Neurosci 1997; 8: 179-93. 268. Nicoll RA, Oliet SH, Malenka RC. NMDA receptordependent and metabotropic glutamate receptordependent forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neurobio Learn Mem 1998; 70: 62-72. 269. Bortolotto ZA, Fitzjohn SM, Collingridge GL. Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus. Curr Opin Neurobiol 1999; 9: 299304. 270. Kemp N, Bashir ZI. Induction of LTD in the adult hippocampus by the synaptic activation of AMPA/kainate and metabotropic glutamate receptors. Neuropharmacology 1999; 38: 495-504. 271. Norris CM, Korol DL, Foster TC. Increased susceptibility to induction of long-term depression and longterm potentiation reversal during aging. J Neurosci 1996; 16: 5382-92. 272. Hsu KS, Huang CC, Liang YC, Wu HM, Chen YL, Lo SW, Ho WC. Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation. Hippocampus 2002; 12: 787-802. 273. Kamal A, Biessels GJ, Gispen WH, Urban IJ. Increasing age reduces expression of long-term depression and dynamic range of transmission plasticity in CA1
field of the rat hippocampus. Neuroscience 1998; 83: 707-15. 274. Lee HK, Min SS, Gallagher M, Kirkwood A. NMDA receptor-independent long-term depression correlates with successful aging in rats. Nat Neurosci 2005; 8: 1657-9. 275. Dunwiddie T, Lynch G. Long-term potentiation and depression of synaptic responses in the rat hippocampus: localization and frequency dependency. J Physiol 1978; 276: 353-67. 276. Dudek SM, Bear MF. Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus. J Neurosci 1993; 13: 2910-8. 277. Norris CM, Halpain S, Foster TC. Reversal of agerelated alterations in synaptic plasticity by blockade of L-type Ca2+ channels. J Neurosci 1998; 18: 3171-9. 278. Kumar A, Foster TC. Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging. Brain Res 2005; 1031: 125-8. 279. Roman FS, Truchet B, Marchetti E, Chaillan FA, Soumireu-Mourat B. Correlations between electrophysiological observations of synaptic plasticity modifications and behavioral performance in mammals. Prog Neurobiol 1999; 58: 61-87. 280. Genoux D, Haditsch U, Knobloch M, Michalon A, Storm D, Mansuy IM. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 2002; 418: 970-5. 281. Braunewell KH, Manahan-Vaughan D. Long-term depression: a cellular basis for learning? Rev Neurosci 2001; 12: 121-40. 282. Diamond DM, Park CR, Campbell AM, Woodson JC. Competitive interactions between endogenous LTD and LTP in the hippocampus underlie the storage of emotional memories and stress-induced amnesia. Hippocampus 2005; 15: 1006-25. 283. Nichols NR, Zieba M, Bye N. Do glucocorticoids contribute to brain aging? Brain Res Rev 2001; 37: 273-86.