Temporal and Cell‐Specific Regulation of Synaptic Homeostasis by the Chromatin Remodeler Chd1

ABSTRACT Disruptions in chromatin remodelers and synaptic proteins represent major genetic risk factors for autism spectrum disorder (ASD), yet how these distinct gene classes converge to impair circuit function remains unclear. CHD2 , a chromatin remodeler linked to ASD, epilepsy, and intellectual disability, regulates gene expression through epigenetic mechanisms. In Drosophila , its homologue Chd1 functions as a key regulator of presynaptic homeostatic potentiation (PHP), a conserved form of synaptic plasticity that stabilizes neurotransmission. Electrophysiology, calcium imaging, super‐resolution microscopy, behavioral assays, and machine learning‐based analysis reveal that Chd1 acts in a temporal and cell type‐specific manner: it is required in perineurial glia for rapid PHP induction and in motoneurons, muscle, and glia for long‐term maintenance. Chd1 controls presynaptic calcium influx and expansion of the readily releasable vesicle pool, both core features of homeostatic compensation. An electrophysiology‐based genetic screen guided by unsupervised machine learning identifies 14 Chd1 ‐dependent genes necessary for acute PHP, including the glial‐specific effector Cadherin 74A . Loss of Chd1 increases seizure susceptibility and disrupts motor function, mirroring phenotypes observed in CHD2 ‐related neurodevelopmental disorders. These findings establish a mechanistic connection between chromatin remodeling and synaptic homeostasis and identify glial epigenetic regulation as a critical modulator of circuit stability in health and disease.