Loss of parvalbumin interneurons and decreased colocalization with perineuronal nets in the dorsomedial striatum of BTBR T+ Itpr3tf/J, idiopathic mouse model of ASD

Abstract

Autism Spectrum Disorder (ASD) is a predominantly idiopathic condition characterised by restrictive, repetitive behaviours and interests (RRBIs) and a deficit in social interaction and communication. Solely from parvalbumin (PV) immunohistochemistry (IHC), the number of parvalbumin-immunoreactive (PV+) GABAergic interneurons has been reported to be decreased across several mouse models of ASD. However, more recent literature disputes for the downregulation of the Ca2+ binding protein PV, not the loss of neurons. These alternatives are anticipated to have opposing effects on excitation/ inhibition (E/I) balance. Although convincingly, PV downregulation has only been reported in transgenic and environmental mice models of ASD. The study of an idiopathic mouse model of ASD, BTBR, which may be considered to have a more human-like aetiology of ASD, will continue to identify convergent molecular endpoints across ASD models and biomarkers which would allow for an earlier diagnosis and intervention. This study used IHC techniques to quantify PV+ cells in the dorsomedial (DMS) and dorsolateral striatum (DLS), regions that were shown to govern goal-directed and habitual behaviour, respectively. Vicia Villosa Agglutinin (VVA) a lectin recognising perineuronal nets (PNNs) which ensheath parvalbumin interneurons was used as a second marker. Student t-tests were carried out and a value of p < .05 was deemed significant. The findings show that female BTBR mice have significantly fewer PV+, and VVA+, cells in the DMS compared to the controls. The decreased counts of PV+ and VVA+ cells suggest that BTBR mice indeed have a loss of parvalbumin interneurons. Consequently, the E/I balance is likely shifted towards diminished inhibition, at least in the DMS region, which may be responsible for symptoms of RRBIs in BTBR mice. Additionally, compared to the controls, female BTBR mice have a significantly reduced PV+VVA+ percentage colocalization in the DMS. Altered colocalization of PV+ cells with PNNs may equally be a result, or the consequence of PV interneuron loss, but may also contribute to symptoms of RRBIs. ASD research should investigate the DMS and DLS as heterogeneous structures.