Soluble α2δ-1, altered in disease CSF, modulates network homeostasis and rescues deficits in a neuropsychiatric mouse...

Excitation-inhibition (E/I) balance depends on dynamic communication between neuronal subtypes, potentially beyond classical neurotransmission. While membrane-bound ion channels are essential for neuronal function, their potential roles as extracellular regulators of network dynamics remain largely unexplored. Here, we identify a soluble form of the voltage-gated Ca²⁺ channel subunit α2δ-1 in human cerebrospinal fluid (CSF) and show that it acts as an activity-regulated intercellular modulator of network homeostasis. Soluble α2δ-1 is reduced in the CSF of individuals with schizophrenia (SZ). Its synthetic analog, synthetic ectodomain of Alpha2Delta-1 (SEAD1), modulates cortical activity by enhancing the function of parvalbumin-positive (PV+) interneurons and restoring E/I balance. A single SEAD1 injection into the prefrontal cortex of a genetic mouse model of SZ reversed synaptic and behavioral deficits, including memory and social impairments. These findings reveal soluble synaptic ectodomains as a previously underappreciated class of extracellular signaling molecules with therapeutic potential in neuropsychiatric disorders.