A pathogenic AMPAR mutation disrupts hippocampal synapse maturation and homeostasis

Abstract

AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are critical for activity-dependent synapse maturation and circuit development. De novo missense mutations in AMPAR subunits are linked to neurodevelopmental disorders (NDDs), yet how these variants disrupt neuronal function remains unclear. Here, we examine a recurrent pathogenic mutation in the GluA1 subunit (GRIA1 p.A636T) that alters AMPAR function and is associated with autism spectrum disorder (ASD) and intellectual disability (ID). Using GluA1A636T knock-in mice of either sex, we identify impairments in hippocampal-dependent learning and working memory. Quantitative proteomics combined with bulk RNA-seq revealed age-dependent molecular remodeling in mutant hippocampus. Synaptic protein alterations were present in juvenile and adult mice, whereas a pronounced upregulation of mitochondrial and glial-associated proteins emerged more strongly in adulthood. Transcriptomic analyses showed partial concordance and highlighted divergence between RNA and protein regulation. Consistent with these molecular changes, there were increases in markers of oxidative stress in juvenile and adult mutant animals, whereas altered mitochondria morphology emerged selectively in adult mutants. Electrophysiological recordings demonstrated reduced basal excitatory transmission, persistence of silent synapses in adulthood and exaggerated activity-dependent synaptic potentiation, which were associated with reduced spine size consistent with impaired synapse maturation. Together, these findings indicate that a pathogenic AMPAR mutation disrupts developmental synapse maturation with secondary metabolic adaptations emerging over time.