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

Alzheimer’s disease (AD) is characterized by hippocampal hyperexcitability and cognitive impairment, in part due to β-amyloid (Aβ)–induced suppression of GABAergic interneuron activity. Enhancing hippocampal inhibition is therefore considered protective, but inhibitory interneurons are highly diverse and not uniformly affected by Aβ. We previously showed that Aβ selectively inhibits α7- and α4β2-nicotinic acetylcholine receptors (nAChRs), but not α3β4-nAChRs, on hippocampal inhibitory interneurons, leading to excitatory neuron hyperactivity, and that co-activation of α7- and α4β2-nAChRs reverses these effects. Here, we demonstrate that α7- and α4β2-nAChRs predominantly regulate cholinergic synaptic activity in parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, respectively. Systemic co-stimulation of these receptors is required to reverse hippocampal hyperexcitability, fear learning-related oscillatory dysfunction, and fear memory loss, and reduce Aβ pathology in AD model mice, indicating that coordinated activation of PV+ and SST+ interneurons via co-activation of α7- and α4β2-nAChRs is required for optimal therapeutic benefit. Teaser Co-activation of selective cholinergic receptors is required to protect Alzheimer’s disease.