Neurobiology of Psychiatric Disorders

Our group explores the neurobiological bases of psychiatric disorders, with a focus on autism, depression, and addiction.

We use multidisciplinary and integrative approaches to study the genetics of autism spectrum disorder (ASD), and two newly identified players in depression and drug addiction, the organic cation transporters (OCT) and matricellular proteins. Our projects both encompass and bridge human studies and animal models, and hence have a strong translational focus.

Our work identifying ASD genes has led to animal models that are then used to decipher the neurobiological mechanisms underlying ASD. Preclinical models in mice have illuminated the role of OCTs in mood-related behaviors and antidepressant efficacy, leading to investigation of their role in treatment-resistant depression in humans and the development of innovative antidepressant drugs targeting these transporters. Preclinical and human studies are also aimed at determining whether the matricellular protein hevin, a novel actor in resilience to stress, could be a relevant biomarker to predict susceptibility to depression and response to treatment.

Genetics of autism

PI: Catalina Betancur

Autism spectrum disorder (ASD) is a behaviorally defined neurodevelopmental disability characterized by impairments in social communication and by restricted and stereotyped behaviors and interests. The genetic architecture of ASD is highly heterogeneous and involves hundreds of loci, each accounting for only a small fraction of cases. To date, a genetic etiology is identified in ~30% of the patients, including chromosomal rearrangements, sequence variants and copy number variants (CNVs). All these abnormalities are rare or even unique; the majority are de novo, consistent with purifying selection against deleterious genetic variants of major effect. Pathogenic variants can also be inherited, and are usually associated with incomplete penetrance or variable expressivity.

The aim of our research is the identification of genes involved in ASD and understanding the pathophysiological mechanisms involved. Our group was among the first to study the contribution of rare sequence variants to the etiology of ASD. Our research and that of our collaborators identified several genes involved for the first time in ASD, such as neurexin NRXN1 (cell adhesion molecule involved in synaptogenesis, presynaptic partner of neuroligins, also implicated in ASD) (Szatmari et al., 2007), SHANK3 (synaptic scaffolding protein, implicated in the 22q13 deletion syndrome/Phelan-McDermid syndrome) (Durand et al., 2007), and SHANK2 (Pinto et al., 2010). Mutations in these genes highlight the crucial role of synapse formation and function in the development of autism and other neuropsychiatric conditions.

We are strongly involved in international consortia performing large-scale analyses of rare structural and sequence variants in ASD, notably the Autism Genome Project and more recently the Autism Sequencing Consortium. For selected candidate genes harboring potentially pathogenic mutations, we perform functional in vitro and in vivo studies to validate their implication in the disorder and to gain insights into the cellular and molecular basis of ASD and related neurodevelopmental disorders. Recently, we used a combination of genetics and functional studies to demonstrate that rare mutations in the GLRA2 gene, encoding the glycine receptor alpha 2 subunit, are associated with ASD and unveiled novel roles for glycine signaling in synaptic plasticity and learning and memory in mice.

Selected references

  • Pilorge M, Fassier C, Le Corronc H, Potey A, Bai J, De Gois S, Delaby E, Assouline B, Guinchat V, Devillard F, Delorme R, Nygren G, Råstam M, Meier JC, Otani S, Cheval H, James VM, Topf M, Dear TN, Gillberg C, Leboyer M, Giros B, Gautron S, Hazan J, Harvey RJ, Legendre P, Betancur C (2016) Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism. Mol Psychiatry 21, 936-945
  • Pinto D, Delaby E […] Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert […] Betancur C*, Scherer SW* (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 94, 677–694 (*equal contribution)
  • Pinto D, Pagnamenta AT […] Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger Jr JI, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368-372

Organic cation transporters as therapeutic targets for mood-related disorders

PI: Sophie Gautron

In the brain, the high-affinity monoaminetransporters are critical for the rapid reuptake of neurotransmitters released into the presynaptic terminals. Consequently, drugs of abuse and antidepressants target these transporters, specifically, dopamine, serotonin or noradrenaline transporters. Our team is studying other categories of monoamine transporters, such as the low-affinity organic cation transporters (OCTs), using multiple approaches. Our previous studies have revealed OCTs as important determinants of aminergic tonus in the brain and of mood-related behaviors, thereby identifying them as novel potential pharmacological targets for the management of depressive disorders. Two OCT subtypes, OCT2 and OCT3 specifically, have been proposed to act as a low-affinity monoamine clearance system, complementing the high-affinity transporters in the brain. There is also substantial evidence that these atypical transporters subserve major central functions, controlling anxiety, response to stress and long-term antidepressant action.

Mood disorders represent widespread and invalidating disorders, with up to 16% of the world population affected by various symptoms of the depression spectrum. However, antidepressants traditionally used to treat major depression disorder, like serotonin and norepinephrine reuptake inhibitors, show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients. Thus, there is at present a pressing need for novel well-tolerated antidepressants.

Our preclinical studies using a validated experimental model of chronic depression demonstrated that in mice the transporter OCT2 is essential for long-term efficacy of standard antidepressants. Ongoing studies aim to characterize the causes of resistance to antidepressant treatment in preclinical models, and to identify genetic and physiological markers of resistant depression in humans, in connection with OCT activity.

We recently demonstrated proof-of-concept that OCTs are relevant therapeutic targets for depression by developing an OCT binding compound with promising antidepressant potential. In a preclinical depression model, this molecule shows rapid positive effects on several behaviors related to depression, with improved action on anhedonia and anxiety as compared to the classical antidepressant fluoxetine. The high therapeutic relevance of these findings is being exploited to develop new, more effective, and safe classes of antidepressants.

Selected references

  • Bacq A, Balasse L, Biala G, Guiard BP, Gardier AM, Schinkel A, Louis F, Vialou V, Martres MP, Chevarin C, Hamon M, Giros B, Gautron S (2012) Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry 17, 926-939
  • Couroussé T, Bacq A, Belzung C, Guiard B, Balasse L, Louis F, Le Guisquet AM, Gardier A, Schinkel A, Giros B, Gautron S (2015) Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3ß signaling. Mol Psychiatry 20, 889-900

Role of the matricellular protein hevin in mood regulation and addiction

PI: Vincent Vialou

Our understanding of neuroplasticity has evolved significantly over the last quarter century. The composition of the extracellular matrix, in particular, was shown to profoundly affect the molecular mechanisms of synaptic plasticity, learning and memory. Matricellular proteins, which include thrombospondins, tenascin C, SPARC and its homolog hevin, represent a relatively unexplored family of proteins that mediate interaction between cells and the extracellular matrix but do not serve primarily structural roles. Most of these proteins are expressed in the brain, where they play an important role during development, in particular in neuronal migration and synaptogenesis. However, their mode of action in adult neuroplasticity is poorly understood. Our team explores the role of matricellular proteins in experience-dependent plasticity and in particular in stress-induced depression and the mechanisms of drug addiction.

Our research has found that hevin is induced by chronic social stress in the nucleus accumbens, a key brain reward region, only in resilient individuals (Vialou et al., 2010). Its overexpression in susceptible mice reversed social avoidance, indicating that induction of hevin is required for resilience to social defeat-induced aversion and anhedonia. Because hevin has anti-adhesive and synaptogenic properties, it could be implicated in the synaptic plasticity underlying positive affect and motivation.

We are now exploring the role of hevin in substance abuse using cell-specific genetic manipulation and pharmaco-genetics combined with behavioral analysis of drug reward. Using double fluorescent in situ hybridization, we recently showed that hevin has a distinct cellular distribution compared to other matricellular proteins. Hevin is prominently expressed in astrocytes and parvalbumin interneurons in both mouse and human adult brains (Mongrédien et al., 2019). We are also using complementary approaches such as in vitro molecular manipulations of hevin on primary cultures to understand how hevin is regulated and activated in astrocytes and neurons.

Selected references

  • Mongrédien R, Erdozain AM, Dumas S, Cutando L, Del Moral AN, Puighermanal E, Rezai Amin S, Giros B, Valjent E, Meana JJ, Gautron S, Callado LF, Fabre V, Vialou V. Cartography of hevin-expressing cells in the adult brain reveals prominent expression in astrocytes and parvalbumin neurons. Brain Struct Funct 2019 Jan 17 [Epub ahead of print]
  • Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, Fallon B, Mazei-Robison M, Ku SM, Harrigan E, Winstanley CA, Joshi T, Feng J, Berton O, Nestler EJ (2014) Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of delta FosB. J Neurosci 34, 3878-87
  • Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, Mouzon E, Rush AJ 3rd, Watts EL, Wallace DL, Iñiguez SD, Ohnishi YH, Steiner MA, Warren BL, Krishnan V, Bolaños CA, Neve RL, Ghose S, Berton O, Tamminga CA, Nestler EJ (2010) DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 13, 745-52