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

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.