March 3, 2026Open Access

A pathogenic AMPA receptor gating mutation disrupts synapse-mitochondrion axis and stalls synapse maturation

Puntos clave

Pathogenic AMPAR gating mutation leads to impaired synapse maturation and altered mitochondrial function in vivo.
In GluA1 A636T mice, hippocampal synaptic transmission is significantly disrupted, resulting in working memory deficits.
Mass spectrometry reveals significant alterations in synaptic and mitochondrial protein expression across developmental stages.
The findings suggest a crucial link between altered synaptic signaling and mitochondrial stress, relevant to glutamate receptor disorders.

Resumen

AMPA receptors (AMPARs) are central regulators of excitatory synaptic transmission and play critical roles in activity-dependent synapse maturation and circuit development. De novo missense mutations in AMPAR subunits have been widely linked to neurodevelopmental disorders (NDDs). Despite this, how these variants lead to neuronal dysfunction remain poorly understood. Here, we investigate the consequences of a recurrent pathogenic mutation in the GluA1 subunit (GRIA1 p.A636T), which alters AMPAR gating properties and is associated with autism spectrum disorder and intellectual disability. We developed a GluA1 A636T knock-in mouse model, we show that GluA1 A636T mice exhibit impairments in hippocampal-dependent learning and working memory accompanied by reduced baseline activity of CA1 neurons in vivo. Mass spectrometry-based quantitative proteomic analyses of juvenile and adult hippocampal samples revealed that the A636T mutation significantly alters synaptic protein expression at both ages. Notably, the mutation drives a robust upregulation of mitochondrial proteins specifically in adult mice. Consistent with this, dendritic mitochondria in adult GluA1 A636T mice exhibited altered morphology and increased oxidative stress. Electrophysiological analyses further revealed abnormalities in synaptic function, including reduced basal excitatory transmission, persistence of functionally silent synapses in adulthood, and altered synaptic plasticity consistent with impaired synapse maturation. Together, these findings demonstrate that a pathogenic AMPAR gating mutation disrupts the coordinated development of synaptic and metabolic programs in the hippocampus, linking altered excitatory signaling to delayed mitochondrial stress and enduring circuit dysfunction. Our study provides a developmental framework for understanding how disease-associated AMPAR variants impair brain function and highlights synapse-mitochondria coupling as a critical axis in glutamate receptor ionotropic (GRI) disorders.

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