Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus

Abstract

Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits.SIGNIFICANCE STATEMENT Memory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

“…A potential explanation lies in the compensation for deletion of M 3 with expression of M 1 receptors (Figure S4) that couple to similar Gq-mediated signalling pathways and it is interesting that knockin mutations of phosphorylation-deficient M 3 receptors with potentially less compensation show greater effects on learning and memory (Poulin et al, 2010). The compensation for M 3 deletion by M 1 receptors is somewhat surprising since M 1 receptors are generally expressed widely in somatic and dendritic cellular domains in pyramidal cells and interneurons where they regulate intrinsic excitability leading to effects on synaptic plasticity and network oscillations (Atherton et al, 2016; Betterton et al, 2017; Buchanan et al, 2010; Dennis et al, 2016; Fisahn et al, 2002; Levey et al, 1995; Mitsushima et al, 2013; Shinoe et al, 2005; Tigaret et al, 2018) but are not generally found in presynaptic terminals (Yamasaki et al, 2010).…”

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

“…S4) that couple to similar Gqmediated signalling pathways and it is interesting that knockin mutations of phosphorylation-deficient M 3 receptors with potentially less compensation show greater effects on learning and memory 67 . The compensation for M 3 deletion by M 1 receptors is somewhat surprising since M 1 receptors are generally expressed widely in somatic and dendritic cellular domains in pyramidal cells and interneurons where they regulate intrinsic excitability leading to effects on synaptic plasticity and network oscillations 12,[14][15][16]51,[68][69][70][71] but are not generally found in presynaptic terminals 72 .…”

Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators

“…Complex pre- and post-synaptic interactions between mGluRs and NMDARs, which reciprocally facilitate receptor function, have been described previously (e.g. Fitzjohn et al, 1996 ; Palmer et al, 1997 ; Krieger et al, 2000 ; Luccini et al, 2007 ; Perroy et al, 2008 ; Tigaret et al, 2018 ; for review see Reiner and Levitz, 2018 ). The molecular mechanisms through which these systems participate in the induction of LTD in juvenile hippocampus remain to be addressed in future studies.…”