Coexistence of Muscarinic Long-Term Depression With Electrically Induced Long-Term Potentiation and Depression at CA3–CA1 Synapses

Abstract

Our laboratory recently characterized a form of long-term depression (LTD) at CA3-CA1 synapses mediated by M1 muscarinic receptors (mAChRs), termed muscarinic LTD (mLTD). mLTD is both activity and NMDAR dependent, characteristics shared by forms of synaptic plasticity thought to be relevant to learning and memory, including long-term potentiation (LTP) induced by high-frequency stimulation (HFS-LTP) and long-term depression induced by low-frequency stimulation (LFS-LTD). However, it remains unclear whether mLTD can occur sequentially with these electrically induced forms of hippocampal plasticity or whether mLTD might interact with them. The first goal of this study was to examine the interplay of mLTD and HFS-LTP. We report that mLTD expression does not alter subsequent induction of HFS-LTP and, further, at synapses expressing HFS-LTP, mLTD can mediate a novel form of depotentiation. The second goal was to determine whether mLTD would alter LFS-LTD induction and/or expression. Although we show that mLTD is occluded by saturation of LFS-LTD, suggesting mechanistic similarity between these two plasticities, saturation of mLTD does not occlude LFS-LTD. Surprisingly, however, the LFS-LTD that follows cholinergic receptor activation is NMDAR independent, indicating that application of muscarinic agonist induces a change in the induction mechanism required for LFS-LTD. These data demonstrate that mLTD can coexist with electrically induced forms of synaptic plasticity and support the hypothesis that mLTD is one of the mechanisms by which the cholinergic system modulates hippocampal function.

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

“…The fEPSP amplitude rapidly returned to the baseline level upon washout of the carbachol. These findings are in agreement with previous data showing that although muscarinic agonists suppress basal synaptic transmission or induce LTD through a presynaptic M1 receptor, they do not affect LTP induction (McCutchen et al, 2006). It is possible that an elevated postsynaptic intracellular Ca 2+ in response to carbachol may partially compensate for the presynaptic depression.…”

Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors

“…2E). Such a synaptic depression may result from the activation of group I mGluR (Palmer et al, 1997;Fitzjohn et al, 1999;Mannaioni et al, 2001) or of mACh receptors (Auerbach and Segal, 1996;Shinoe et al, 2005;McCutchen et al, 2006;Dickinson et al, 2009). After transient suppression by GYKI 53655, EPSPs were not persistently enhanced at 60 min, whether interneurons were hyperpolarized to Ϫ80 to Ϫ100 mV (n ϭ 4) or not (n ϭ 3).…”

“…Activa- tion of either receptor affects transient and persistent K ϩ currents. We tested possible effects on the voltage trajectory after interneuron firing (Benardo and Prince, 1982;Greene et al, 1994;Kawasaki et al, 1999;McQuiston and Madison, 1999;Ireland and Abraham, 2002) and on the steady-state membrane potential (Cole and Nicoll, 1983;Madison et al, 1987;Crépel et al, 1994;Guérineau et al, 1995;Howe and Surmeier, 1995;Mannaioni et al, 2001;Lawrence et al, 2006a).…”

“…Because extracellular stimulation has been used in most studies, LTP of these synapses has not been examined in isolation in paired recordings. We recorded from synaptically coupled pyramidal cells and stratum oriens interneurons (Ali and Thomson, 1998;Losonczy et al, 2002) to characterize this synapse and the factors controlling its long-term plasticity (Fig. 7).…”

“…Although Hebbian LTP is conventionally presented as a glutamate receptor narrative, it is modulated by other transmitters. Thus aminergic systems enhance LTP (Thomas et al, 1996;Lin et al, 2003) via second-messenger effects on glutamate receptor trafficking.…”