Abstract

The α7 nicotinic acetylcholine receptor (α7nAChR) is one of the most abundant nicotinic acetylcholine receptors in the brain and has been extensively studied for over three decades. Owing to its high calcium permeability, the α7nAChR has been primarily linked to the regulation of synaptic functions, such as synaptic transmission and synaptic plasticity. Importantly, due to the reduced expression of α7nAChRs in patients with schizophrenia as well as genetic links between CHRNA7 (coding for α7nAChR) and the cognitive impairments of schizophrenia, α7nAChR has been the leading drug target for improving cognitive functions in schizophrenia and other neurological disorders. However, while a dozen of α7nAChR-targeting drugs have been tested in clinical trials, none has made it to the market due to their limited efficacy and side effects. This indicates that there is a gap of knowledge in the cellular and molecular mechanisms that underlie the pro-cognitive value of α7nAChRs. Past studies of α7nAChRs have exclusively focused on neurons. However, α7nAChRs are ubiquitously expressed on various cell types including glial cells such as astrocytes. Astrocytes are increasingly recognized as active participants in the brain, controlling synaptic function, circuit activity, and behavior. Interestingly, astrocytic α7nAChRs were shown to control the availability of D-serine, a co-agonist that is required alongside glutamate for the activation of synaptic N-methyl D-aspartate receptors (NMDARs). However, the importance of this astrocyte-based α7nAChR signaling pathway to behavior has not been explored. Taking an agnostic approach, I first explored the cell-specific contributions of α7nAChRs to behavior. I found that mice selectively lacking α7nAChRs in astrocytes exhibited profound deficits across cognitive domains captured by the MATRICS (measurement and treatment research to improve cognition in schizophrenia) Consensus Cognitive Battery (MCCB). This includes disruptions in semantic memory, social cognition, vocalization and spatial learning. In addition, this coincided with lowered D-serine levels in the brain of these mice and, importantly, supplementing D-serine through drinking water restored behavioral performance. Furthermore, in line with past findings that α7nAChR-mediated astrocytic supply of D-serine is time-of-day dependent, I found that the behavioral impairments of astrocyte-specific α7nAChRs KO mice were absent in the light phase (Zeitgeber Time 6, ZT6). Interestingly, the deficits of astrocyte-specific α7nAChRs KO mice were limited to cognitive domains assessed by the MCCB, with no alteration in other behaviors such as locomotion and sleep architecture. By contrast, the behavior of excitatory neuron and inhibitory neuron-specific α7nAChRs KO mice was largely unaltered in MCCB-related behavioral domains. Using two-photon laser scanning microscopy, I also showed that α7nAChR stimulation with a specific agonist (PNU-282987) increased calcium activity in astrocytes, likely through direct calcium influx rather than the intracellular calcium store. This response was abolished in the presence of a selective antagonist (methyllycaconitine, MLA) or in astrocyte-specific α7nAChRs KO mice, consistent with the high calcium permeability of α7nAChRs. Last, I showed that an α7nAChR partial agonist previously evaluated as a cognitive enhancer in Phase III schizophrenia and AD clinical trials augmented behaviors in control mice but was ineffective in mice lacking α7nAChRs in astrocytes. Altogether, these findings identify astrocytes and D-serine/NMDAR signaling as a core mechanism through which the α7nAChR, a major drug target, promotes normal and drug-enhanced cognitive functions.

Committee Chair

Thomas Papouin

Committee Members

Erik Herzog; Susan Maloney; Xinzhu Yu; Yao Chen

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-1-2026

Language

English (en)

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Available for download on Sunday, July 30, 2028

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