Parvalbumin-Expressing Interneurons in the BTBR T+ Itpr3tf/J Idiopathic Mouse Model of Autism Spectrum Disorder

Abstract

Parvalbumin (PV)-expressing inhibitory interneurons are considered critical in regulating excitation/inhibition (E/I) balance and have gained particular interest in the aetiology of autism spectrum disorder (ASD). Dysfunction of the dorsal striatum has been profoundly associated with ASD aetiology, regions which are involved in goal-directed and habitual behaviour in the dorsomedial (DMS) and dorsolateral striatum (DLS), respectively. Perineuronal nets (PNNs) are extracellular structures which predominantly surround PV+ interneurons and contribute to their fast-spiking properties. Utilising the BTBR T+ Itpr3tf/J (BTBR) mouse model of ASD, we investigated whether this idiopathic strain exhibits a reduced expression of PV. Through immunohistochemistry, we observed that BTBR mice had a reduced density of PV+ interneurons in the DMS, whilst density of PNNs was unaltered. The percentage of VVA+ cells with PV expression as well as PV levels were found to be significantly decreased, suggesting that BTBR mice present with a downregulation of PV expression in the DMS. We observed that control mice have a greater percentage of PV+ interneurons with PNNs in the DLS than in the DMS, however, BTBR mice were found to not possess such a gradient. We also observed that colocalisation of PV+ interneurons with PNNs in the dorsal striatum was higher in female BTBR mice than in male counterparts. This sex difference was not evident in control mice. PV downregulation may be a common endpoint of ASD aetiology in an idiopathic, and other, mouse models of ASD. Alterations in the colocalisation of PV+ interneurons with PNNs alongside PV reduction have been shown to alter neuronal function and we anticipate that such may also alter E/I balance in BTBR mice. Differences which prevail between sexes in BTBR mice highlight the importance of considering sex in the aetiology of ASD and BTBR may be a particular robust strain to further investigate this.