Implication of the 5-HT7 receptor in the paradoxical pro-depressant effects of SSRIs during development

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

Congreso; FENS Virtual Forum; 2020

FENS

Enhanced vulnerabilityto emotional disorders, such as anxiety and depression, can result from altereddevelopmental trajectories during early life. Remarkably, antidepressants thatact as selective serotonin reuptake inhibitors (SSRIs) and have beneficialeffects in adulthood , have unwanted long-term effects like risk for anxietyand depression when administered during the neonatal period. We previouslyidentified neurons in the prefrontal cortex (PFC) that transiently express theserotonin transporter (SERT: Slc6a4) and showed that genetic or pharmacologicalblockade caused exuberant glutamatergic synapses in the dorsal raphe nucleus(DRN) (Soiza-Reilly et al. 2019). To identify upstream molecular actors engagedin these effects, we focused on serotonin receptors (Htr). Based on geneexpression profiling we identified, Htr7 as a possible candidate. We found thatHtr7 is transiently co-expressed with SERT in deep cortical layers of the mousePFC during early postnatal development. We used a combination of genetic andpharmacological approaches to explore the developmental role of Htr7 inemotional behaviors and its interaction with SSRIs. Overexpression of Htr7 inthe PFC was sufficient to induce increased glutamatergic synapse formation inthe DRN as well as a pro-depressant phenotype. Finally, both genetic andpharmacological inhibition of HTR7 during development prevented the long termpro-depressive and anxiogenic impact of postnatal FLX.Conclusions : Htr7 is transiently expressed in deep corticallayers of the PFC, where it controls synaptic maturation of cortical projectionsto the DRN. Htr7 is required for the negative paradoxical emotional effects inadults that result from SSRIs administration during the neonatal period.<!-- /* 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:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536859905 -1073697537 9 0 511 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:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:ES;}p{mso-style-noshow:yes;mso-style-priority:99;mso-margin-top-alt:auto;margin-right:0cm;mso-margin-bottom-alt:auto;margin-left:0cm;mso-pagination:widow-orphan;font-size:12.0pt;font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}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;}