Assessing Expression and Function of Serotonin Receptors and Transporter in Fmr1 Knockout Mice

Abstract

The serotonin receptors (5-HTRs) and transporter (SERT) modulate excitation-inhibition altered in autism and its leading monogenic cause, fragile X syndrome (FXS). Here, we assessed their expression and function in adult Fmr1 knockout (KO) mice, a model of FXS, compared to wild type (WT) mice. We performed autoradiography on brain sections using [3H]5-CT for 5-HT1ARs, [3H]Ketanserin for 5-HT2ARs, [3H]Mesulergine for 5-HT2CRs, [3H]Citalopram for SERT. Regions of interest were analyzed using ImageJ. Saturation binding assay was performed for 5-HT1ARs with [3H]5-CT. Behavioral effects of 1,2mg/kg (R)-8-OH-DPAT, 1 mg/kg (�)-DOI, 1,3,10mg/kg lorcaserin and 10mg/kg escitalopram were used to probe in vivo functional activity of 5-HT1A, 5-HT2A, 5-HT2CRs, and SERT, respectively. KO males have higher 5-HT1AR expression in lateral septum and frontal cortex, lower 5-HT2AR expression in isocortex layer V and lower 5-HT2CR expression in anterior olfactory nucleus and nucleus accumbens, than WT males. Saturation binding analysis confirmed the increased 5-HT1AR expression. WT and KO males had lower 5-HT2CR expression in choroid plexus and caudate putamen than females. KO mice showed more pronounced responses to (R)-8-OH-DPAT, decreased DOI-elicited head twitches, and similar lorcaserin-induced hypolocomotion compared to WT mice. SERT expression and function are being evaluated. This shows perturbations in key 5-HTRs in Fmr1 KO mice, suggesting dysfunctions in the central 5-HT system in FXS.