Postnatal refinement of synaptic afferents to dorsal raphe 5-HT neurons: Implications for psychiatric disorders

*ADJIMANN, T S.; *ARGAÑARAZ, C V.; FERNANDEZ, S.P.; BARIK, J.; PERISSINOTTI, P.P.; SOIZA REILLY, M.

Tampa

Congreso; American College of Neuropsychopharmacology Meeting; 2023

ACNP

Background: Serotonin (5-hydroxytryptamine, 5-HT) neurons areimplicated in the etiology and therapeutics of anxiety anddepression. Critical periods of vulnerability during brain develop-ment enable maladaptive mechanisms to produce detrimentalconsequences on adult mood. 5-HT plays a pivotal role in thesemechanisms, however, little is known about how synaptic inputsshaping the activity of 5-HT networks mature during postnataldevelopment. We investigated in mice the postnatal trajectory ofglutamate and GABA synaptic inputs to dorsal raphe nucleus(DRN) 5-HT neurons, a main source of forebrain 5-HT.Methods: In C57BL/6 and Swiss mice (both sexes) we applied amultidisciplinary approach combining high-resolution morpholo-gical analyses (array tomography) together with ex-vivo patch-clamp recordings and pharmacology. Data were analyzed bymultifactorial ANOVA followed by Tukey’s comparisons.Results: Our results showed that cortical glutamate synapsesundergo a profound refinement process between the third andfourth postnatal weeks (p<0,05), while subcortical glutamateinputs do not. Next, we asked whether this neurodevelopmentalprocess could be altered in a mouse model of early-life emotionalvulnerability. In this model, a brief exposure to fluoxetine(p.o.10mg/kg/day) during the first two postnatal weeks results inlong-lasting depressive-like and anxiety behaviors. We found thatfluoxetine-treated mice (both sexes) had a selective increase incortical synaptic inputs to 5-HT neurons as early as the followingday after the treatment cessation (p < 0,05 vs. sucrose-treated mice).Conclusions: This suggests that postnatal fluoxetine exposurecould enhance the synaptogenic potential of cortical inputsinfluencing the early activity of 5-HT neurons. Our studycontributes to the understanding of neurodevelopmental vulner-ability to psychiatric disorders.@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;}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";}.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;}div.WordSection1{page:WordSection1;}