Deficiency of calretinin in prefrontal cortex causes behavioral deficits relevant to autism spectrum disorder in mice.

Scientists studied a brain protein called calretinin in mice to understand autism better. They found that when this protein was reduced in a brain area important for behavior, mice showed autism-like symptoms including social difficulties, repetitive behaviors, anxiety, and memory problems. The brain cells also became overactive. This research helps explain one possible biological reason why some autism symptoms occur.

This preclinical study investigated the role of calretinin (CR), a protein found in specific brain cells, in autism spectrum disorder using mouse models. Researchers found reduced CR levels in the prefrontal cortex of mice with prenatal valproic acid exposure (an established autism model). When CR was experimentally reduced in healthy mice using viral vectors, the animals displayed autism-like behaviors including social impairments, repetitive behaviors, increased anxiety, and memory problems. Electrophysiological recordings revealed that CR deficiency increased neuronal excitability in prefrontal cortex neurons.

The findings suggest CR deficiency may contribute to autism-like symptoms through altered brain cell activity, providing new insights into potential biological mechanisms underlying autism spectrum disorder.

Results suggest calretinin-positive interneurons may be therapeutic targets for autism interventions. However, this is preclinical research requiring human validation. Findings support excitation-inhibition imbalance theories in autism and may inform future drug development targeting GABAergic systems.

Sample sizes not reported. Single animal model study limits generalizability to human autism. Viral knockdown approach may not fully replicate natural calretinin deficiency patterns. Long-term effects of intervention unknown.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, repetitive and stereotyped behaviors, along with higher levels of anxiety and cognitive impairments. Previous studies demonstrate pronounced reduced density of calretinin (CR)-expressing GABAergic interneurons in both ASD patients and animal models. The object of the current study was to determine the role of CR in ASD-relevant behavioral aberrations. Herein, the mRNA and protein levels of CR in the prefrontal cortex (PFC) of mouse model of ASD based on prenatal exposure to valproic acid (VPA) were determined by qRT-PCR and Western blot analysis, respectively.

Moreover, the behavioral abnormalities in naive mice with CR deficiency mediated by recombinant adeno-associated virus (rAAV) were evaluated in a comprehensive testing battery including social interaction, marble burying, self-grooming, open-field, elevated plus maze and novel object recognition tests. Furthermore, the action potential changes caused by CR deficiency were examined in neurons within the PFC in naive mouse. The results show that the mRNA and protein levels of PFC CR of VPA-induced mouse ASD model were reduced. Concomitantly, mice with CR knockdown displayed ASD-like behavioral aberrations, such as social impairments, elevated stereotypes, anxiety and memory defects.

Intriguingly, patch-clamp recordings revealed that CR knockdown provoked decreased neuronal excitability by increasing action potential discharge frequencies together with decreased action potential threshold and rheobase. Our findings support a notion that CR knockdown might contribute to ASD-like phenotypes, with the pathogenesis most likely stemming from increased neuronal excitability.