Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer's disease

Abstract

Beta-amyloid peptide (A{beta})-induced suppression of hippocampal GABAergic interneuron activity drives hyperexcitability, amyloid pathology, and cognitive impairment in Alzheimers disease (AD), suggesting that enhancing hippocampal inhibition may be protective. However, hippocampal interneurons are highly diverse and differentially regulate inhibition and cognition, making it challenging to identify the affected subtypes and optimally restore hippocampal inhibition in AD. We have previously found that A{beta} selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, 7- and 4{beta}2-nAChRs, but not 3{beta}4-nAChRs, and inhibits these two receptors in hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation in excitatory neurons. Here, we further reveal that 7- and 4{beta}2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. We also find that systemic co-stimulation of 7- and 4{beta}2-nAChRs is required to reverse hippocampal hyperexcitability, dysfunction of fear learning-associated hippocampal oscillatory activity, and hippocampus-dependent memory loss and reduce A{beta} pathology in AD model mice. This suggests that co-stimulation of PV+ and SST+ cells via activation of 7- and 4{beta}2-nAChRs together is required to enhance hippocampal inhibition optimally, which reverses hippocampal dysfunction, reduces amyloid pathology, and ultimately prevents memory loss in AD. Significance StatementDevelopment of a safe and effective unified strategy to counteract hyperexcitability holds a significant promise in advancing Alzheimers disease (AD) treatment. Studies suggest that beta-amyloid peptide (A{beta}) is a major trigger of hyperexcitability. However, the mechanisms of how A{beta} could participate in hyperexcitability are still not fully understood. Here, we reveal that A{beta} inhibits distinct hippocampal nicotinic acetylcholine receptor (nAChR) subtypes in different hippocampal inhibitory interneuron subtypes, which leads to hyperexcitability, resulting in amyloid pathology and memory loss in AD. We further discover that systemic co-stimulation of these nAChRs is required for neuroprotection against AD at the cellular, circuit, network, and behavioral levels. Identifying this mechanism can thus provide a new therapeutic strategy in AD.