NMDAR dysfunction in autism spectrum disorders: Lessons learned from 10 years of study.

Scientists have spent 10 years studying mouse models of autism to understand what causes the condition. They found that problems with brain receptors called NMDA receptors might be important in autism, but not all autism models show these problems. This suggests autism has many different causes, not just one. Researchers need to consider many factors like genes, age, sex, and different brain areas when studying autism.

This review examines a decade of research on NMDA receptor (NMDAR) dysfunction in autism spectrum disorder mouse models. While numerous mechanisms have been proposed at molecular, synaptic, neuronal, circuit, and systems levels, no single mechanism applies universally, reflecting ASD's heterogeneous nature. NMDAR dysfunction has received significant attention, with hypofunction more common than hyperfunction across mouse models. However, not all models show NMDAR dysfunction, suggesting either non-universal presence or incomplete understanding of NMDAR-related abnormalities in ASD.

The review emphasizes considering multiple variables when studying ASD models, including genetic mutations, deletion dosage, background, sex, age, brain regions, cell types, and neural circuits.

Findings suggest autism's complexity requires consideration of multiple biological pathways rather than single mechanisms. This supports need for personalized research approaches and potentially individualized interventions based on specific neurobiological profiles.

This is a narrative review without systematic methodology reported. No specific sample sizes or quantitative analysis provided. Findings are based on mouse models which may not fully translate to human autism.

Over the past decade or so, mouse models of autism spectrum disorders (ASD) have been extensively studied in the search for key mechanisms underlying the disorder. Numerous intriguing mechanisms have been proposed, spanning various levels of the neural system, including molecular, synaptic, neuronal, circuit, and systems-level processes. However, no single mechanism has emerged as universally applicable, highlighting the heterogeneous nature of the genetic and neurobiological underpinnings of ASD. Among these, the NMDA receptor (NMDAR) dysfunction hypothesis has garnered significant attention.

Many mouse models exhibit NMDAR dysfunction, with NMDAR hypofunction appearing more prevalent than hyperfunction. Nevertheless, not all mouse models display this dysfunction, suggesting that NMDAR abnormalities may not be ubiquitous across models, or that we have yet to fully explore the spectrum of NMDAR-related dysfunction in ASD. These findings underscore the need to consider multiple factors when studying ASD mouse models, including different mutations within the same gene, gene deletion dosage, genetic background, sex, age, brain regions, cell types, and neural circuits.