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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The aim now in Dr Cardinaux’s lab is to study these mice in different situations, further identify the brain regions and circuits, which are involved in depressive behaviour and uncover more detail about the underlying mechanisms involved in mood disorders. Several behavioural tests have been approved for investigating depression in animals, one of which is called the sucrose preference test. “You present two bottles – one with just water, and the other with a little bit of sucrose mixed in the water – and you monitor what the mice drink,” explains Dr Cardinaux. Usually there’s a marked preference for the sucrose solution, but this is reduced in mice that are experiencing anhedonia. “This test is quite subtle, but a reduced preference is recognised as a measure of anhedonia,” continues Dr Cardinaux. “We are also looking at social behaviour. We’ve seen in our mouse model that mood is affected at different levels in the males. It can lead to aggressive behaviour, while it may also affect social interaction. These symptoms are very interesting in terms of understanding the neurobiological basis of depression.”
Role of the CREB coactivator CRTC1 in mood disorders and antidepressant response Project Objectives
Project team (from left to right): Jean-René Cardinaux, Laetitia Guiraud, Clara Rossetti, and Antoine Cherix.
there’s a link between atypical depression and obesity, and our colleagues have discovered that CRTC1 polymorphisms may be playing a role in this association.” A lot of attention in research is also focused on the antidepressant response. Researchers have found that the mice in which CRTC1 is inactivated do not respond to conventional antidepressants. “This suggests that CRTC1 is involved in the response to the conventional antidepressants, it needs to be there,”
We’ve seen in our mouse model that mood is affected at different levels in the males. It can lead to aggressive behaviour, while it may also affect social interaction. Mood disorders are often associated with metabolic syndrome and circadian rhythm disturbances. “We’ve found that male mice lacking CRTC1 not only display depressivelike behaviours, their circadian locomotor activity and feeding behaviour are altered as well, leading to obesity,” says Dr Cardinaux. “Our mouse model is very interesting to study as it associates many symptoms of major depression and its related disorders.”
Translational research
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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The wider aim is to establish clearer links between these findings and human depression, which could then open up new possibilities in terms of translational research. Regarding CRTC1 levels in the brain, Dr Cardinaux hopes in future to look at postmortem tissue material of the human brain, which could help establish links between the animal models and human depression. “We want to see if there’s a decrease of CRTC1 in regions like the hippocampus or the prefrontal cortex,” he outlines. Research is also continuing into gene polymorphisms that could be linked to depression. “We’ve been collaborating with a group here at our institute who are working on the genetics of obesity, linked to psychiatric disorders,” continues Dr Cardinaux. “It’s been shown that
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says Dr Cardinaux. A new antidepressant called ketamine is now emerging, which Dr Cardinaux says could overcome some of the problems associated with conventional antidepressants. “It takes several weeks before conventional antidepressants become active. The advantage of ketamine is that it can be active after just a few hours,” he explains. “We’ve tried treating our mice with ketamine, and we’ve found that the rapid response to a single dose of ketamine is preserved in CRTC1 knockout mice. This suggests that CRTC1 is not necessarily required for the rapid antidepressant effect of ketamine, but we plan to investigate its role in the long-lasting effects of ketamine.” This is a topic Dr Cardinaux plans to explore further in future, while he is also interested in helping to develop new antidepressants that would act on this CRTC1 pathway. Increasing, or restoring, CRTC1 levels could represent a route towards more effective antidepressants, yet Dr Cardinaux says new therapeutic approaches need to be built on a detailed understanding of the underlying basis of depression. “We would have to study and to know how those CRTC1 levels are decreased by chronic stress, and find the mechanisms. If you understand the mechanisms, maybe then you can help restore those levels,” he says.
Major depression is a still poorly understood psychiatric condition that affects millions of people worldwide. Preclinical studies with animal models of depression provide a better understanding of the mechanisms involved in its etiopathogenesis. Mice lacking a transcription coactivator called CRTC1 constitute a new and interesting animal model of depression, exhibiting several behavioral and molecular alterations related to human depression and associated disorders. The project focuses on further characterizing the consequences of CRTC1 deficiency on mood disorders-related symptoms and antidepressant response.
Project Funding
Funded by the Swiss National Science Foundation. Grant 31003A_170126. “Role of the CREB coactivator CRTC1 in mood disorders and antidepressant response”.
Contact Details
Dr. Jean-René CARDINAUX, PhD Centre de Neurosciences Psychiatriques Département de Psychiatrie Route de Cery 11b CH-1008 Prilly T: +41 (0)21 314 3596 E: Jean-Rene.Cardinaux@chuv.ch W: www.chuv.ch/cpn-molecularpsy Saura, CA and Cardinaux JR (2017). Emerging Roles of CREB-Regulated Transcription Coactivators in Brain Physiology and Pathology. Trends Neurosci. 40, 720-733, doi:10.1016/j.tins.2017.10.002.
Dr. Jean-René CARDINAUX, PhD
Dr Jean-René Cardinaux is a senior lecturer and group leader at the Center for Psychiatric Neuroscience and Service of Child and Adolescent Psychiatry of the Lausanne University Medical Center (CHUV), Switzerland. He holds a PhD in molecular biology from the University of Lausanne (UNIL) and gained postdoctoral experience in molecular neuroscience, first at UNIL and then at the Vollum Institute of the Oregon Health & Science University in Portland, USA. His main research interests focus on the transcriptional control of neuroplasticity genes and the mechanisms underlying their altered expression in depression.
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