Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer's disease
Lee, R.; Kim, G.; Kim, S.
Show abstract
Alzheimers disease (AD) is characterized by hippocampal hyperexcitability and cognitive impairment, in part due to {beta}-amyloid (A{beta})-induced suppression of GABAergic interneuron activity. Enhancing hippocampal inhibition is therefore considered protective, but inhibitory interneurons are highly diverse and not uniformly affected by A{beta}. We previously showed that A{beta} selectively inhibits 7- and 4{beta}2-nicotinic acetylcholine receptors (nAChRs), but not 3{beta}4-nAChRs, on hippocampal inhibitory interneurons, leading to excitatory neuron hyperactivity, and that co-activation of 7- and 4{beta}2-nAChRs reverses these effects. Here, we demonstrate that 7- and 4{beta}2-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 A{beta} pathology in AD model mice, indicating that coordinated activation of PV+ and SST+ interneurons via co-activation of 7- and 4{beta}2-nAChRs is required for optimal therapeutic benefit. TeaserCo-activation of selective cholinergic receptors is required to protect Alzheimers disease.
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