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

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.