Leora Ojadi

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting early-age development of social skills, communication, and behavior, in addition to executive function. Despite numerous individual differences, phenotypical profiles are characterized by two distinct features: social communication deficits and repetitive sensory-motor behaviors. In the United States, it is estimated that every 1 out of 36 individuals has ASD.¹ While its etiology and pathogenesis remain unclear, there is overwhelming evidence to suggest a strong genetic component. Several genes have been implicated in its course (MECP2, PTEN, and FMR1 to name a few), thus yielding an estimated 40-90% heritability.² Epigenetic and environmental factors are also believed to play a significant role, including maternal health/exposures and DNA methylation.^3,4 Aripiprazole and risperidone are currently the only FDA approved pharmacotherapies and are typically used to address extreme irritation and agitation.⁵ The popular theory of its etiology focuses on the excitatory-inhibitory balance of glutamate and GABA, which is believed to be correlated to the severity of social deficits.³ By extension, NMDA receptor modulation to fine-tune glutamate signaling has been hypothesized to show significant effect on these deficits. These findings could further elucidate the mechanisms underlying ASD phenotypes and potential therapies.

Objective: In this narrative review, we explored the role NMDA receptors play in the presentation of social deficits via gene knockout and subsequent rescue of function/reduction of deficits via NMDA receptor-acting drugs.

Methods: This review was completed using a comprehensive search across PubMed. The initial PubMed MeSH search keywords used were (((autism spectrum disorder)) AND (“NMDA receptor”). Additional searches were conducted by adding the terms (“glutamate”) and (“NMDA antagonist”). Only publications with a date of publication within the range of 2015 to 2026 were eligible. Articles with little relevance to glutamate modulation were excluded.

Results: Elevated glutamate levels were found to be directly correlated to the severity of social deficits.^6,7 In one study, direct NMDA receptor antagonism via ketamine was found to reduce the severity of ASD-like social deficits in MeCP2 KO mouse models.⁶ A randomized clinical trial showed similar results from NMDA antagonism via memantine in children.⁷ Conversely, NMDA receptor rescue also produced significant results.^8-10 Genes implicated in NMDA receptor assembly and function (Shank3, FMR1, and Dock4) produced social deficits when knocked out, which were consequently saved by different methods. Dock4 KO social deficits were improved with restored Rac1 activity, which regulates formation of excitatory synapses.⁹  Shank3 KO social deficits were rescued via a ketogenic diet, which produced beta-hydroxybutyrate, a histone deacetylase inhibitor that ultimately stabilized receptor scaffolding proteins at glutamatergic post-synaptic clefts.¹⁰  Positive NMDA receptor allosteric modulator zelquinstel was also successful in relieving social deficits.⁸

Conclusion: The studies show potential for NMDA receptor mechanisms as both a causative source of symptoms and a therapeutic target. The contradictory nature of the studies’ results suggests that rather than there being one clear answer as to whether glutamate elevation or depression causes social deficits, there is a delicate balance that must be achieved and maintained in the central nervous system for deficits to not occur. The future of ASD treatments may lie in already available medications. However, the complex nature of ASD requires an approach that considers all factors involved before considering pharmacological intervention.

Works Cited

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