Astrocytes transform the transcriptomic and epigenetic landscape of developing cortical neurons to promote activity via intrinsic excitability control

Astrocytes are implicated in neuronal development and function, particularly of synapses, but their genome-wide impact is unclear. We show that cortical astrocytes trigger epigenetic remodelling in developing cortical neurons and widespread transcriptomic changes distinct from neurons’ intrinsic developmental trajectory. These changes can cause an emergence of neuronal firing activity independent of functional excitatory synaptogenesis. The mechanism is via through astrocyte-derived signals causing the transcriptional repression of inwardly-rectifying K ⁺ -channels (Kirs), causing a pro-excitatory shift in intrinsic properties. This places neurons in a zone of excitability whereupon cell-autonomous homeostatic control was activated, also associated with Kir regulation. Astrocyte-induced neuronal genes were enriched for schizophrenia, epilepsy, ADHD and Alzheimer’s disease risk, disorders associated with circuit imbalance. Thus, astrocyte-to-neuron signaling can alter firing via intrinsic properties in addition to the classical synaptogenic mechanism. The opposing actions of astrocytes and neuronal activity in regulating neuronal intrinsic properties may prevent hyper- or hypo-activity in neuronal circuits