Muscarinic Induction of Hippocampal Gamma Oscillations Requires Coupling of the M1 Receptor to Two Mixed Cation Currents

Abstract

Oscillatory network activity at gamma frequencies is assumed to be of major importance in cortical information processing. Whereas the synaptic mechanisms of gamma oscillations have been studied in detail, the ionic currents involved at the cellular level remain to be elucidated. Here we show that in vitro gamma oscillations induced by muscarine require activation of M1 receptors on hippocampal CA3 pyramidal neurons and are absent in M1 receptor-deficient mice. M1 receptor activation depolarizes pyramidal neurons by increasing the mixed Na(+)/K(+) current I(h) and the Ca(2+)-dependent nonspecific cation current I(cat), but not by modulation of I(M). Our data provide important insight into the molecular basis of gamma oscillations by unequivocally establishing a novel role for muscarinic modulation of I(h) and I(cat) in rhythmic network activity.

Characterization of a CNS penetrant, selective M1muscarinic receptor agonist, 77‐LH‐28‐1

“…In these studies, 77-LH-28-1 induced a pirenzepine-sensitive depolarization, suggesting that it produced this response by activation of M 1 mAChRs. Furthermore, 77-LH-28-1 stimulated gamma frequency oscillations in rat hippocampus, a response that is reported to be absent in M 1 mAChR knockout mouse hippocampus (Fisahn et al, 2002). These data further support that this synchronous network activity may be important for cellular processes underlying cognitive function and that it is mediated by M 1 mAChRs (Wynn et al, 2005).…”

“…Indeed, mAChR activation has been shown to induce gamma oscillations (Fisahn et al, 1998), and knockout mouse studies have implicated the M 1 mAChR receptor subtype as playing a major role in the initiation of such network activity (Fisahn et al, 2002). We therefore tested whether 77-LH-28-1 would initiate network oscillations in the rat hippocampus in vitro.…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…For example, ACh acts through M1 receptors that are coupled to the Ins(1,4,5)P 3 /Ca 2+ signaling pathway, which functions to regulate the excitability of both hippocampal and dentate gyrus neurons. 2,3 Variations in the activity of this arousal system, which is translated into variations in the tonic excitatory drive, determines the hierarchy of the neural rhythms with the lowest frequencies occurring during sleep (i.e., the slow waves and delta rhythms) that then switch to the higher frequency theta and gamma rhythms of the wake state (Fig. 1).…”

“…Such global elevations in Ca 2+ may also act to enhance membrane depolarization by stimulating an inward Ca 2+ current (I CAN ). 2,8 Norepinephrine and dopamine also contribute to the tonic excitatory drive by acting through the cyclic AMP signaling pathway to enhancing the activity of the hyperpolarizingactivated cyclic nucleotide-gated (HCN) channel responsible for the I h current (Fig. 1).…”

Analysis of CD8+ T cell-mediated anti-viral responses in mice with targeted deletions of the M1 or M5 muscarinic cholinergic receptors

“…Mice with targeted deletions of the M 1 or M 5 receptors (Fisahn et al, 2002;Yamada et al, 2001) were backcrossed onto C57BL/6 mice at Taconic labs, for at least 10 generations. Wildtype C57BL/6 mice were purchased from Taconic labs.…”