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

The Role of Kv7 Channels in Neural Plasticity and Behavior

“…Consistently, muscarinic agonist improves whereas anticholinergic agent scopolamine impairs performance in hippocampus-dependent memory tasks (Fontana et al, 1994;Fontan-Lozano et al, 2011). Muscarinic acetylcholine receptors in the prefrontal cortex also modulate working memory in primates via K v 7 channels (Galvin et al, 2020). Since cholinergic depletion and dysfunction in the hippocampus and prefrontal cortex are implicated in age-related cognitive decline and Alzheimer's disease (Ballinger et al, 2016;Haam and Yakel, 2017), these studies support the therapeutic potential for K v 7 antagonists as cognitive enhancers.…”

“…The postsynaptic role of K v 7 channels is unclear. A recent electron microscopy study shows that K v 7.2, K v 7.3, and K v 7.5 colocalize with muscarinic acetylcholine receptors at dendritic spines in layer III pyramidal neurons of the primate prefrontal cortex (Galvin et al, 2020), although the specificity of the immunolabeling needs to be further validated. In the CA1-CA3 synapses, the mEPSC amplitude is unaltered by agonist nor antagonists of K v 7 channels (Sun and Kapur, 2012), suggesting their negligible role in regulating postsynaptic glutamate receptor function at this synapse ( Figure 1A).…”

Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species

“…Nic-α7R are particularly effective in fluxing Ca 2+ ( Fucile, 2004 ), which may help to sustain membrane depolarization needed for continuous firing. A more recent study by Wang and Galvin showed that muscarinic M1R also permits NMDAR Delay cell firing, possible exciting the synaptic membrane via closure of synaptic KCNQ “m” channels, and/or by increasing internal Ca 2+ release via Gq-IP3 signaling ( Galvin et al, 2020 ). As acetylcholine is released during waking but not deep sleep, this unusual form of synaptic transmission may explain why dlPFC microcircuits can communicate during waking to allow conscious mental activity, but not during deep sleep when we are unconscious.…”

“…Early studies with Jane Taylor showed that activation of cAMP-PKA signaling in rat mPFC impaired working memory performance ( Taylor, Birnbaum, Ubriani, & Arnsten, 1999 ), opposite to its enhancing effects on long-term memory consolidation in hippocampus and amygdala. Ultrastructural analysis of the primate layer III dlPFC by Paspalas and colleagues showed a constellation of cAMP-related proteins near the Ca 2+ -containing spine apparatus (the extension of the smooth endoplasmic reticulum into the spine), near HCN and KCNQ channels, providing structural evidence for feedforward Ca 2+ -cAMP-K + channel signaling in layer III dlPFC spines ( Carlyle et al, 2014 , Galvin et al, 2020 , Paspalas et al, 2013 , Wang et al, 2007 ). Thus, rapid changes in cAMP-Ca 2+ -K + channel signaling can produce dynamic changes in synaptic strength to coordinate environmental events and arousal with cognitive state, a process termed Dynamic Network Connectivity ( Arnsten et al, 2012 ).…”

Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex

“…High concentrations of the cholinergic agonist, carbachol (CCh; >10 µM), lead to a potent enhancement of sADP that is mediated, in part, through PLC-dependent actions on TRPCs (Egorov et al, 2002;Reboreda et al, 2018;Yan et al, 2009). However, lower concentrations of CCh more accurately reflect physiological levels of cholinergic receptor activation (Galvin et al, 2020;Marrosu et al, 1995). We postulated that netrin-1 may facilitate persistent firing activity in the presence of low concentrations of CCh (5 µM).…”