Muscarinic M1 Receptors Modulate Working Memory Performance and Activity Via KCNQ Potassium Channels in Primate Prefrontal Cortex

Abstract

Working memory relies on dorsolateral prefrontal cortex (dlPFC), where microcircuits of pyramidal neurons enable persistent firing in the absence of sensory input, maintaining information through recurrent excitation. This activity critically relies on acetylcholine, though the molecular mechanisms for this dependence are not thoroughly understood. The current study investigated the role of muscarinic M1 receptors (M1R) in dlPFC using iontophoresis coupled with single unit recordings from aging monkeys with naturally-occurring cholinergic depletion. We found that M1R stimulation produced an inverted-U dose response on cell firing, with enhancing effects mediated via closure of KCNQ potassium (“M”) channels. Immunoelectron microscopy localized KCNQ isoforms (Kv7.2, Kv7.3, Kv7.5) on layer III dendrites and spines, similar to M1R. Finally, systemic administration of a M1R positive allosteric modulator produced an inverted-U dose response, enhancing working memory performance at low doses. These results indicate M1R may be an appropriate target to treat cognitive disorders with cholinergic alterations.

Keywords: Acetylcholine, muscarinic, M1, cholinergic, prefrontal cortex, dorsolateral prefrontal cortex, working memory, aging, schizophrenia, KCNQ