Astrocytes mediate the pro-cognitive value of α7nAChRs and of α7nAChR-targeting therapeutics.

The α7-nicotinic acetylcholine receptor (α7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimer's disease (AD). Yet, a systematic evaluation of the role played by α7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that α7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of α7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an α7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic α7nAChRs. Together, these findings identify astrocytes and D-serine/NMDAR signaling as a central mechanism through which α7nAChR, a major drug target, promotes cognitive behavior.