Sarcosine Is Increased in an Autism cohort and Drives Memantine-Reversible Behavioral and Gene Expression Changes in Young Mice

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with alterations in metabolism and excitatory–inhibitory (E/I) balance, yet the functional consequences of specific metabolic changes remain unclear. From previous published reseach articles on metabolic studies of ASD individuals, similarly our metabolic study data identified a significant elevation of sarcosine, a glycine-derived modulator of NMDA receptor signaling. To investigate its functional relevance, we examined the effects of chronic sarcosine administration in adult and young mice. Sarcosine induced anxiety-like behavior, impaired sociability, decreased grooming, and increased depression-like behavior, without affecting motor function. Most of these effects were seen only in young mice treated with sarcosine. These findings indicate a developmental vulnerability to sarcosine. Pharmacological blockade of NMDA receptors with memantine attenuated sarcosine-induced anxiety, social deficits, and depression-like behavior, but did not rescue grooming deficits or elevated corticosterone levels, suggesting both NMDA-dependent and independent mechanisms. Transcriptomic analysis of the frontal cortex revealed widespread gene expression changes induced by sarcosine, including pathways related to synaptic function and neurodevelopment, many of which were normalized by memantine. In contrast, mitochondrial-related gene alterations were not rescued. Together, these findings identify sarcosine as a metabolite elevated in ASD that can drive autism-related behavioral and molecular phenotypes in a development-dependent and partially NMDA receptor–dependent manner.