Risperidone impedes glutamate excitotoxicity in a valproic acid rat model of autism: Role of ADAR2 in AMPA GluA2 RNA editing.

Researchers studied how the medication risperidone works in rats with autism-like behaviors. They found that autism-related brain changes involved problems with how brain cells process a chemical messenger called glutamate. Risperidone helped fix these problems and improved the rats' behavior. This gives scientists new ideas about how risperidone might help people with autism.

This preclinical study investigated risperidone's effects on RNA editing mechanisms in a valproic acid (VPA) rat model of autism. The research examined how chronic risperidone treatment affects ADAR2 expression, AMPA receptor GluA2 editing, and cellular markers of neuronal death. Results showed that prenatal VPA exposure caused autism-like behaviors and reduced ADAR2 expression, leading to impaired GluA2 RNA editing and increased neuronal death markers. Risperidone treatment (1-3mg) improved behavioral deficits, restored ADAR2 expression, enhanced GluA2 editing, and reduced oxidative stress and neurodegeneration.

The study suggests a novel mechanism by which risperidone may benefit autism through correcting RNA editing deficits that contribute to glutamate excitotoxicity.

While promising for understanding risperidone's mechanisms, these preclinical findings require human validation. The RNA editing pathway may represent a new therapeutic target, but clinical translation remains uncertain. Current risperidone prescribing practices should continue following established guidelines pending human studies.

Animal model findings may not directly translate to humans. Sample size not reported. Single study without replication. Unclear if behavioral improvements correlate directly with molecular changes. Limited to specific VPA autism model which may not represent all autism presentations.

Several reports indicate a plausible role of calcium (Ca) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker "caspase-3" and a decrease in the antiapoptotic marker "BCL2" alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing.

This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.