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

OLUSAKIN J; MOUTKINE I; DUMAS S; PONIMASKIN E; PAIZANIS E; SOIZA REILLY M; GASPAR P

Virtual

Conferencia; Molecular Mechanisms of Neuronal Connectivity CSHL Meeting; 2020

Cold Spring Harbor Laboratory

Altereddevelopment of prefrontal cortex (PFC) circuits can have long-term consequenceson adult emotional behavior. Changes in serotonin homeostasis during criticalperiods produced by genetic or pharmacological inactivation of the serotonintransporter (SERT, or Slc6a4), has been involved in such developmental effects.In mice, serotonin selective reuptake inhibitors (SSRIs), administered during postnataldevelopment cause exuberant synaptic connectivity of the PFC to brainstemdorsal raphe nucleus (DRN) circuits, and increase adult risk for developinganxiety and depressive symptoms. SERT is transiently expressed in the glutamateneurons of the mouse PFC, that project to the DRN. Here, we find that 5-HTR7 istransiently co-expressed with SERT by PFC neurons, and it plays a key role in thematuration of PFC-to-DRN synaptic circuits during early postnatal life.5-HTR7-KO mice show reduced PFC-to-DRN synaptic density (as measured byarray-tomography and VGLUT1/synapsin immunocytochemistry). Conversely, 5-HTR7over-expression in the developing PFC increased PFC-to-DRN synaptic density.Long-term consequences on depressive-like and anxiogenic behaviors wereobserved in adults. 5-HTR7 over-expression in the developing PFC, results indepressive-like symptoms in adulthood. Importantly, the long-termdepressive-like and anxiogenic effects of SSRIs (postnatal administration of fluoxetinefrom P2 to P14) were not observed in 5-HTR7-KO mice, and were prevented byco-administration of the selective inhibitor of 5-HTR7, SB269970. This study identifiesa new role 5-HTR7 in the postnatal maturation of prefrontal descendingcircuits. Furthermore, it shows that 5-HTR7 in the PFC is crucially requiredfor the detrimental emotional effects caused by SSRI exposure during earlypostnatal life. <!-- /* Font Definitions */ @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Cambria;panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-1610611985 1073741899 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";mso-fareast-language:FR;}p.Corps, li.Corps, div.Corps{mso-style-name:Corps;mso-style-unhide:no;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;border:none;mso-border-alt:none white 0cm;padding:0cm;mso-padding-alt:31.0pt 31.0pt 31.0pt 31.0pt;font-size:12.0pt;font-family:"Cambria",serif;mso-fareast-font-family:"Times New Roman";mso-bidi-font-family:Cambria;color:black;mso-ansi-language:EN-US;mso-fareast-language:FR;text-underline:black;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:10.0pt;mso-ansi-font-size:10.0pt;mso-bidi-font-size:10.0pt;}size:612.0pt 792.0pt;margin:70.85pt 70.85pt 70.85pt 70.85pt;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}