Rescuing Neurodevelopmental Deficits in AMPA Receptor Gain-of-Function Mutant

Chen, C.-M.; Huang, Y.-M.; Chung, C.-C.; Johnson, R. C.; Tsai, C.-Y.; Chen, Y.-H.; Tan, H. L.; Hsiao, F.-Y.; Huganir, R. L.; Chiu, S.-L.

doi:10.64898/2025.12.30.697121

bioRxiv · 10.64898/2025.12.30.697121

Rescuing Neurodevelopmental Deficits in AMPA Receptor Gain-of-Function Mutant

Chen, C.-M.·Huang, Y.-M.·Chung, C.-C.·Johnson, R. C.·Tsai, C.-Y.·Chen, Y.-H.·Tan, H. L.·Hsiao, F.-Y.·Huganir, R. L.·Chiu, S.-L.

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Abstract

AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are essential for neuronal development and brain function. We investigated the role of a recurrent variant in the AMPAR GluA1 subunit (GRIA1 p.A636T) identified in individuals with autism spectrum disorder (ASD) and intellectual disability (ID). To test causality and mechanism, we generated a Gria1-A636T knock-in mouse model. Mutant mice exhibited core ASD/ID-like behaviors and a selective hippocampal vulnerability characterized by progressive dendritic atrophy and neuronal loss. Despite reduced GluA1-containing complexes, AMPARs displayed synaptic hyperexcitability and failed to undergo the normal postnatal transition to calcium-impermeable AMPARs, resulting in persistent excitotoxicity. To explore therapeutic intervention, we designed an allele-specific antisense oligonucleotide to specifically silence the mutant transcript. A single neonatal administration of the antisense oligonucleotide entirely prevented hippocampal pathology and ameliorated behavioral deficits. These findings establish GRIA1-A636T as a gain-of-function mutation that drives developmental excitotoxicity and highlight the potential of RNA-targeted precision medicine for neurodevelopmental disorders.

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Chen, C.-M., Huang, Y.-M., Chung, C.-C., Johnson, R. C., Tsai, C.-Y., Chen, Y.-H., Tan, H. L., Hsiao, F.-Y., Huganir, R. L., Chiu, S.-L.. 2025-12-31. Rescuing Neurodevelopmental Deficits in AMPA Receptor Gain-of-Function Mutant. https://doi.org/10.64898/2025.12.30.697121

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