Hypoactivity, abnormal development of dendrites relevant to impaired synaptic transmission of calretinin-expressing interneurons in the medial prefrontal cortex underlies social deficits of mouse model in autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairments in social behavior and communication. The impaired excitatory and inhibitory signals have been implicated in the pathophysiology of social behavior deficits. Altered calretinin (CR)-containing GABAergic interneurons have been observed in ASD, but their roles and underlying mechanisms remain unveiled. Here, using valproic acid (VPA)-exposed mice for CR-Cre and R26::LS-tdTomato (Ai14) model of ASD, we prove that a decreased number of CR interneurons in the mPFC of an animal model for ASD. Double-staining experiments demonstrated the decreased number of CR interneurons stained for c-Fos. Also, reduction in GCaMP7s fluorescence intensity was elicited in sociability and social novelty preference using in vivo fiber photometry, manifesting VPA-induced suppression of CR-positive cell activation. Additionally, we observed the abnormalities of dendrites in CR interneurons including lower dendritic arbors, decreased dendrite complexity, and spine density, paralleled by abnormal development of spine morphology. Intriguingly, the electrophysiological recordings of tdTomato-labeled interneurons revealed that exposure to VPA depressed intrinsic neuronal excitability by decreasing spontaneous and evoked action potential frequencies. These changes were concomitant with impairments of glutamatergic and GABAergic synaptic transmission of CR interneurons. Strikingly, chemogenetic silencing of mPFC CR-expressing interneurons induced social interaction deficits in mice. These sociability impairments can be rescued by optogenetic activation of CR activity in VPA-exposed mice. Our study indicates that prenatal exposure to VPA induced reduced activities, abnormalities in morphological development, and decreased intrinsic excitability as well as accompanying impaired synaptic transmission of CR interneurons. Our findings provide strong evidence for the notion that the CR interneurons has a critical role in the regulation of social behavior in mice and manifest that CR interneurons dysfunction may be implicated in social impairments in ASD.