Parvalbumin and perineuronal net expression in the medial and lateral regions of the dorsal striatum in an idiopathic model of ASD, through development and between sexes.

Abstract

Introduction
Parvalbumin-expressing fast-spiking interneurons (PV+FSIs) within the dorsal striatum, associated with the generation of habitual behaviour and motor stereotypy, are a commonly reported node of alteration in autism spectrum disorders (ASDs). However previous investigations of altered striatal PV+FSIs and associated perineuronal nets (PNNs) in ASD lack consideration of potential differences in expression between dorsostriatal subregion, sex, and developmental stage. The aim of this study was to investigate potential alterations in the density, colocalisation, and molecular profile of PV+FSIs and PNNs in the dorsal striatum of an idiopathic model of ASD (BTBR T+Itpr3tf/J mice) relative to control C57 L/J mice with consideration to subregion (dorsomedial striatum, dorsolateral striatum), sex (male, female), and developmental stage (3-4wk, 6-8wk).
Methods
and Statistical Analysis This study utilised immunohistochemical methodology on tissue from BTBR T+Itpr3tf/J(n=20) and C57 L/J(n=20) mice. The density of PV+FSIs and PNNs, their colocalisation, and relative intensity of fluorescent staining within the dorsal striatum was compared between mouse strain, subregion, sex, and developmental stage. Statistical analysis was performed in R Studio. Post-normality assessment data was analysed via 4-way mixed ANOVA, with post-hoc analysis performed via Tukey’s HSD test.
Results
A significantly lower density of PV+FSIs and colocalised PNN+PV+FSIs were observed within the dorsomedial striatum of BTBR T+Itpr3tf/J mice relative to C57 L/J mice (F(1,58)= 21.6, p=.0134; F(1,58)=8.56, p=.007). Whilst a significant reduction in the density of PV+FSIs through development was identified in C57 L/J mice, no significant difference in PV+FSI density between developmental stages was noted in BTBR T+Itpr3tf/J mice (F(1,58)= 18.9, p=.000138; p=.400). Further, a greater basal density of PV+FSIs within the dorsomedial striatum was observed in male mice relative to female mice (F(1,58)=25.91, p=.0002) whereas a greater basal density of PV+FSIs was observed in female mice within the dorsolateral striatum (p=.0427). A greater basal density of colocalised PNN+PV+FSIs in the dorsolateral striatum was also observed in female mice (F(1,58)= 9.99, p < .0001).
Conclusions
These findings may suggest that the reduced density of striatal PV+FSIs often reported in ASDs to be largely explained by downregulation within the dorsal striatum. Further, identification of sex differences in the expression PV+FSIs and colocalised PNN+PV+FSIs in a subregion-dependent manner highlights the importance of considering sex in investigations of ASD aetiology.