Uncovering new insights into depression Depression affects millions of people across the world, yet the underlying neurobiological causes of the condition are still not fully understood. We spoke to Dr Jean-René Cardinaux about his research into the molecular mechanisms and regions of the brain linked with depressive behaviour, which could in future lead to improved treatment. A number of
hypotheses have been developed to identify the root cause of depression, yet the underlying factors behind the development of mood disorders are still unclear. Most of the current hypotheses are based on the response to antidepressants. “Most conventional antidepressants act on monoamine neurotransmitters, mostly serotonin and noradrenaline. The monoamine hypothesis suggests that a depletion of those neurotransmitters leads to depression,” explains Dr Jean-René Cardinaux, a researcher in molecular psychiatry and epigenetics based at Lausanne University Hospital. However, it typically takes several weeks before antidepressants become active, suggesting that other factors are also involved, beyond the rapid restoration of the level of these neurotransmitters. “So that’s why other hypotheses have been put forward,” says Dr Cardinaux. The neurotrophic hypothesis of depression for example suggests that a specific class of stress hormones called glucocorticoids have a negative impact on neurotrophic factors, a topic at the heart of Dr Cardinaux’s research. These neurotrophic factors are a class of biomolecules that support neurons in the brain. “These neurotrophic factors support neuron survival as well as neurogenesis. One factor that has been shown to be important is called brain-derived neurotrophic factor (BDNF),” says Dr Cardinaux. As the Principal Investigator of a SNSF-funded project, Dr Cardinaux aims to help build a clearer picture of the etiopathogenesis of mood disorders, which could have important implications in terms of treatment. “It was previously shown that a transcription factor called CREB can regulate the expression of BDNF,” he outlines. “We’ve found that a coactivator of CREB called CRTC1 seems to also play an important role in this regulation.”
Model of depression By studying a mouse model in which CRTC1 has been inactivated, Dr Cardinaux and his colleagues aim to gain deeper insights into both depression and also the associated pathological conditions. A variety of symptoms are associated with
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Possible role of the transcription coactivator CRTC1 in the pathogenesis of depression and associated disorders.
depression, including anhedonia, or an inability to feel pleasure, while there are also physical symptoms. “For instance, weight gain or weight loss can occur depending on the depression subtypes. Psychomotor retardation can also be observed, where people feel tired and lethargic, with a visible slowing of physical and emotional reactions” says Dr Cardinaux. It has been shown that
mice in which CRTC1 has been inactivated show certain symptoms associated with depression and mood disorders, now Dr Cardinaux is looking to probe deeper. “In our mouse model we see a decrease in BDNF expression, but also of other genes. The phenotype of these mice have similarities with depression – we call it a depressive-like phenotype,” he explains.
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