A cholinergic trigger drives learning-induced plasticity at hippocampal synapses

Dai Mitsushima,Akane Sano,Takuya Takahashi

doi:10.1038/ncomms3760

Abstract

Learning induces plastic changes in synapses. However, the regulatory molecules that orchestrate learning-induced synaptic changes are largely unknown. Although it is well established that cholinergic inputs from the medial septum modulate learning and memory, evidence for the cholinergic regulation of learning-induced synaptic plasticity is lacking. Here we find that the activation of muscarinic acetylcholine (ACh) receptors (mAChRs) mediates the contextual fear learning-driven strengthening of hippocampal excitatory pyramidal synapses through the synaptic incorporation of AMPA-type glutamate receptors (AMPARs). Contextual fear learning also enhances the strength of inhibitory synapses on hippocampal pyramidal CA1 neurons, in a manner mediated by the activation of, not mAChRs, but, nicotinic AChRs (nAChRs). We observe a significant correlation between the learning-induced increases in excitatory and inhibitory synaptic strength at individual pyramidal neurons. Understanding the mechanisms underlying cholinergic regulation of learning-induced hippocampal synaptic plasticity may help the development of new therapies for cognitive disorders.

Highlights

We found that ACh mediates learning-induced strengthening at excitatory and inhibitory synapses through distinct sets of ACh receptors (AChRs), revealing novel molecular and cellular mechanisms of learning-dependent synaptic plasticity
We previously revealed that the synaptic delivery of GluA1containing AMPA-type glutamate receptors (AMPARs) in the CA1 is required for contextual memory[16]
It is largely accepted that the amount of paired-pulse facilitation (PPF) is inversely related to the initial release probability[24,25]

Summary

Introduction

We find that the activation of muscarinic acetylcholine (ACh) receptors (mAChRs) mediates the contextual fear learning-driven strengthening of hippocampal excitatory pyramidal synapses through the synaptic incorporation of AMPA-type glutamate receptors (AMPARs). Contextual fear learning enhances the strength of inhibitory synapses on hippocampal pyramidal CA1 neurons, in a manner mediated by the activation of, not mAChRs, but, nicotinic AChRs (nAChRs). The cholinergic modulation of synaptic plasticity is well described, including in long-term potentiation (LTP), a cellular model of learning and memory[1,5,6,7,8] It is still unclear whether ACh mediates the learning-induced synaptic changes. IA learning strengthens inhibitory hippocampal synapses through the activation of nAChRs but not mAChRs. Further, we find significant correlation between the IA-induced increase in miniature excitatory post-synaptic current (mEPSC) and mIPSC amplitudes at individual pyramidal neurons. ACh balances the excitatory and inhibitory synaptic inputs onto CA1 pyramidal neurons in IA learning through the activation of distinct sets of AChRs

Methods

Results

Conclusion