Neuronal Aralar/AGC1 deficiency impairs social behavior through dopaminergic and redox dysfunction and is rescued by β-hydroxybutyrate

Neuron-specific Aralar/AGC1 deletion in mice causes hyperactivity and a marked sociability deficit, linked to reduced striatal dopamine content and oxidative stress, and is rescued by β-hydroxybutyrate.

• Why it matters: Pathogenic SLC25A12/AGC1 variants are associated with ASD, but how neuronal metabolic failure translates into social-behavior changes is unclear.
• What they did: The study used CamKII-Cre to delete Aralar postnatally in cortex, hippocampus, and striatum, then tested adult behavior, transcriptomics, neurochemistry, and oxidative stress, with systemic β-hydroxybutyrate treatment.
• The result: Despite normal growth and cognition, Neu Aralar-KO mice showed 55–65% lower forebrain Aralar expression, 433 differentially expressed genes, reduced striatal DA with increased DOPAC/DA, elevated lipid peroxidation, and astrocyte activation; β-hydroxybutyrate restored sociability and normalized metabolic, redox, and genotype-dependent neurochemical abnormalities.

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