Synergistic Actions of Metabotropic Acetylcholine and Glutamate Receptors on the Excitability of Hippocampal CA1 Pyramidal Neurons

Abstract

A variety of neurotransmitters are responsible for regulating neural activity during different behavioral states. Unique responses to combinations of neurotransmitters provide a powerful mechanism by which neural networks could be differentially activated during a broad range of behaviors. Here, we show, using whole-cell recordings in rat hippocampal slices, that group I metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChRs) synergistically increase the excitability of hippocampal CA1 pyramidal neurons by converting the post-burst afterhyperpolarization (AHP) to an afterdepolarization (ADP) via a rapidly reversible upregulation of Cav2.3 R-type calcium channels. Co-activation of mAChRs and mGluRs also induced a long-lasting enhancement of the responses mediated by each receptor type. These results suggest that cooperative signaling via mAChRs and group I mGluRs could provide a mechanism by which cognitive processes may be modulated by conjoint activation of two separate neurotransmitter systems.

Gi/o protein‐coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission

“…We first investigated the effects on neurons of endogenous G q GPCR activation by acetylcholine (ACh), which activates muscarinic ACh receptors (mAChRs). Type 1, 3, and 5 mAChRs, known to be coupled to G q proteins, are highly expressed in hippocampal neurons (Berkeley et al, ; Park & Spruston, ; Scheiderer et al, ). We performed whole‐cell electrophysiological recordings from hippocampal CA1 pyramidal neurons, monitored neuronal Ca 2+ levels, and locally applied ACh (Figure a).…”

“…We first investigated the effects on neurons of endogenous G q GPCR activation by acetylcholine (ACh), which activates muscarinic ACh receptors (mAChRs). Type 1, 3, and 5 mAChRs, known to be coupled to G q proteins, are highly expressed in hippocampal neurons (Berkeley et al, 2001;Park & Spruston, 2012;Scheiderer et al, 2008). We per- To confirm the effects of G q signaling in neurons, we selectively expressed G q DREADDs in hippocampal CA1 pyramidal neurons using the viral vector AAV5-CaMKIIα-hM3Dq-mCherry, which contains the G q DREADD and the fluorescent reporter mCherry under the CaMKIIα promoter, which is highly expressed in CA1 pyramidal neurons (Erondu & Kennedy, 1985;Schulman & Lou, 1989).…”

Neuromodulation of neurons and synapses

“…If these effects have the same sign, they can either be occluding, i.e. simply additive [85], or synergistic [86 •• ]. …”

Cholinergic connectivity: it's implications for psychiatric disorders

“…However, prefrontal cortical cholinergic afferents were not regulated by AMPA signaling from the parietal cortex, suggesting that the glutamatergic control is unidirectional. Further evidence for co-regulation comes from Group1 mGluRs acting in conjunction with muscarinic receptors to produce long lasting increases in excitatory postsynaptic potentials (Park and Spruston, 2012), possibly via protein kinase C (PKC)-mediated activation of Src tyrosine kinase (Lu et al, 1999). This co-regulation is supported by reports that co-administrating carbachol and rolipram, a phosphodiesterase inhibitor which prevents cAMP inhibition, produces long lasting increases in hippocampal excitatory postsynaptic potentials associated with brain derived neurotrophic factor-dependant long term potentiation (Navakkode and Korte, 2012).…”