Abstract
Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.
Highlights
The term autism spectrum disorder (ASD) is used to describe a series of heritable neurodevelopmental disorders with a heterozygous presentation that can present in the form of abnormal communication, social interaction, repetitive behaviors, and restricted interests
We began by conducting Western blotting assays to assess metabotropic glutamate receptor 7 (mGluR7) protein levels in the prefrontal cortex (PFC) of valproic acid (VPA)-treated and BTBRT+ Itpr3tf/J (BTBR) ASD model mice
We found that VPA exposure was linked with a significant reduction in mGluR7 protein expression in the PFC relative to levels in control animals (p < 0.05, Figure 1A)
Summary
The term autism spectrum disorder (ASD) is used to describe a series of heritable neurodevelopmental disorders with a heterozygous presentation that can present in the form of abnormal communication, social interaction, repetitive behaviors, and restricted interests. Five isoforms of metabotropic glutamate receptor 7 (mGluR7), which is encoded by GRM7, have been found to be expressed in the prefrontal cortex (PFC) in mammals (Millán et al, 2003; Wang et al, 2018a), and prior research has linked GRM7 mutations to ASD incidence (Xia et al, 2015; Fisher et al, 2018; Yang et al, 2019). Increased neuronal excitability is thought to be critical for many of the behavioral and functional phenotypes characteristic of ASD (Takarae and Sweeney, 2017; Lo and Erzurumlu, 2018; Hajisoltani et al, 2019). The specific mechanistic role for mGluR7 as a regulator of neuronal excitability and ASD-related behavioral abnormalities remains to be fully clarified
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