Implication of 5-HT7 receptor in prefrontal circuit assembly and detrimental emotional effects of SSRIs during development

Altered development of prefrontal cortex (PFC) circuits can have long-term consequences on adult emotional behavior. Changes in serotonin homeostasis during critical periods produced by genetic or pharmacological inactivation of the serotonin transporter (SERT, or Slc6a4), have been involved in such developmental effects. In mice, selective serotonin reuptake inhibitors (SSRIs), administered during postnatal development cause exuberant synaptic connectivity of the PFC to brainstem dorsal raphe nucleus (DRN) circuits, and increase adult risk for developing anxiety and depressive symptoms. SERT is transiently expressed in the glutamate neurons of the mouse PFC, that project to the DRN. Here, we find that 5-HTR7 is transiently co-expressed with SERT by PFC neurons, and it plays a key role in the maturation of PFC-to-DRN synaptic circuits during early postnatal life. 5-HTR7-KO mice show reduced PFC-to-DRN synaptic density (as measured by array-tomography and VGLUT1/synapsin immunocytochemistry). Conversely, 5-HTR7 over-expression in the developing PFC increased PFC-to-DRN synaptic density. Long-term consequences on depressive-like and anxiogenic behaviors were observed in adults. 5-HTR7 over-expression in the developing PFC, results in depressive-like symptoms in adulthood. Importantly, the long-term depressive-like and anxiogenic effects of SSRIs (postnatal administration of fluoxetine from P2 to P14) were not observed in 5-HTR7-KO mice, and were prevented by co-administration of the selective inhibitor of 5-HTR7, SB269970. This study identifies a new role 5-HTR7 in the postnatal maturation of prefrontal descending circuits. Furthermore, it shows that 5-HTR7 in the PFC is crucially required for the detrimental emotional effects caused by SSRI exposure during early postnatal life.Fil: Olusakin, Jimmy. Sorbonne University; Francia. Inserm; Francia. University of Geneva; SuizaFil: Moutkine, Imane. Inserm; Francia. Sorbonne University; FranciaFil: Dumas, Sylvie. Oramacell; FranciaFil: Ponimaskin, Evgeni. Hannover Medical School; AlemaniaFil: Paizanis, Eleni. Inserm; Francia. Universite de Caen Basse Normandie; FranciaFil: Soiza Reilly, Mariano. Sorbonne University; Francia. Inserm; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Gaspar, Patricia. Sorbonne University; Francia. Inserm; Francia. Institut du Cerveau et de la Moëlle; Franci

Sérotonine et comportements émotionnels : rôle du développement du récepteur 5-HT7

Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during developmental periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. In a previous study, we identified a subpopulation of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC) that transiently expressed Slc6a4/SERT during an early postnatal period in mice (P0–P10). These PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Genetic ablation of SERT or early-life exposure to the SSRI, fluoxetine (from P2 to P14), increases the number of functional PFC glutamate synapses (hyperinnervation) on both 5-HT and GABA neurons in the DRN which also causes anxiety/ depressive-like symptoms. From our transcriptomic profiling of these PFC-SERT+ neurons at a developmental age of P7, we identified the Htr7 gene which could be mediating the developmental effects of SERT ablation. In this thesis, using anatomical and behavioural assays, I showed that pharmacological blockade of the 5-HT7 receptor using specific antagonist was sufficient to prevent the hyperinnervation to the DRN and the anxiety/depressive-like symptoms. In addition, we showed that the 5-HT7 knockout mice have no morphological and behavioural deficits. Furthermore, overexpression of 5-HT7 in the developing PFC, was sufficient to reproduce the anxiety/depressive-like symptoms observed in the absence of PFC-SERT. In conclusion activation of the PFC 5-HT7 receptor during development, could be responsible for the hyperinnervation of glutamatergic synapses to DRN and therefore precipitates the depressive-like behaviours.Les antidépresseurs qui bloquent le transporteur de sérotonine (Slc6a4 / SERT) améliorent l'humeur chez l'adulte, mais ont des effets paradoxaux sur le développement à long terme, augmentant le risque de développer l'anxiété et la dépression. La base de cet effet sur le développement n'est pas connue. Dans une étude précédente, nous avions identifié une sous-population de neurones pyramidaux de la couche corticale préfrontal 5 (PFC) qui exprimaient de manière transitoire le SERT au cours d'une période postnatale précoce chez la souris (P0 - P10). Ces neurones PFC-SERT + établissent des synapses glutamatergiques avec des cibles sous-corticales, y compris le noyau du raphé dorsal (DRN). L'ablation génétique du SERT ou une exposition précoce à la fluoxétine provoque une hyperinnervation synaptique chez DRN, qui provoque également des symptômes d'anxiété / dépressifs. Nous avons identifié le gène Htr7 qui pourrait médier les effets du SERT sur le développement. En utilisant des tests anatomiques et comportementaux, je montre que le blocage pharmacologique du récepteur 5-HT7 est suffisant pour prévenir une hyperinnervation à la DRN et des symptômes similaires à ceux de l'anxiété / dépression. De plus, nous avons montré que les souris knock-out 5-HT7 ne présentaient aucun déficit morphologique et comportemental. De plus, la surexpression de 5-HT7 dans les PFC en développement était suffisante pour reproduire les symptômes d'anxiété / dépressifs observés en l'absence de PFC-SERT. En conclusion, l'activation du récepteur PFC 5-HT7 au cours du développement peut être responsable de l'hyperinnervation synaptique dans le DRN et précipite ainsi les comportements dépressifs

Impact du stress neonatal sur l'oligodendrogénèse du cortex préfrontal et du comportement adulte. Identification de mécanismes activité dépendants

International audienceExposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC), and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here, we focused on changes induced by chronic maternal separation during the first 2 weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first 2 postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalised it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short-term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early-life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviours