Coactivation of M₁Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

Abstract

Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M 1 or adrenergic ␣1 receptors induces activity-and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common G␣q-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M 1 and ␣1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signalregulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M 1 and ␣1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M 1 and ␣1 receptors could function to induce long-term changes in synaptic function important for cognition.

Distinct forms of G q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

“…These results, in conjunction with the differing mEPSC and sEPSC profiles, strongly suggest that although the same cell contains the required elements for the induction of either α 1 -AR or mGluR5 LTD, they occur by distinctly different mechanisms. Furthermore, the induction of one form of G q -coupled LTD manipulates the plasticity of the other LTD (19), which differs from observations in other brain regions, where dual G q -coupled LTDs have been studied (17,18). It is possible to envision that the occlusion of mGluR LTD in the BNST by α 1 -AR LTD could influence subsequent behavior, and a lack of proper α 1 -AR LTD induction/expression (see below) may result in pathological mGluR LTD expression.…”

“…A particularly interesting feature of α 1 -AR LTD is that it is heterosynaptic in nature in that it does not occur by augmenting NMDA receptor or mGluR5 signaling, although it can be elicited in the same neurons in BNST as mGluR5-LTD (19). Based on this interaction and the studies in hippocampus (17) and visual cortex (18), we hypothesized that α 1 -AR LTD and mGluR5 LTD share common mechanisms and are recruited by similar environmental stimuli. Here, we demonstrate that contrary to our hypothesis, α 1 -AR LTD but not mGluR5 LTD results in the loss of functional calcium-permeable AMPA receptors (CP-AMPARs) from the synapse, suggesting distinct mechanisms.…”

“…Furthermore, multiple drugs of abuse hijack plasticity mechanisms at glutamatergic synapses in the BNST (13)(14)(15) and other reward nuclei (16). At hippocampal and cortical synapses, long-term depression (LTD) of excitatory transmission elicited by G q -coupled GPCRs has been suggested to operate through a common pathway (17,18). Previously, we described that mGluR5 activation induces LTD of excitatory transmission in the BNST (13).…”

O-GlcNAcylation of AMPA Receptor GluA2 Is Associated with a Novel Form of Long-Term Depression at Hippocampal Synapses

“…Preparation of hippocampal slices (400 m) from 3-to 4-week-old male and female Sprague Dawley rats and extracellular dendritic field EPSP (fEPSPs) recordings from CA3-CA1 synapses (Axoclamp 2B; Molecular Devices) followed previously published methods (Smith and McMahon, 2005;McCutchen et al, 2006;Scheiderer et al, 2008).…”

“…The high-frequency stimulation (HFS) protocol used to induce NMDAR-dependent LTP consisted of four 0.5 s trains of 100 Hz stimuli separated by 20 s (Smith andMcMahon, 2005, 2006). LTD induction.…”