Muscarinic Receptors, from Synaptic Plasticity to its Role in Network Activity

Acetylcholine acting via metabotropic receptors plays a key role in learning and memory by regulating synaptic plasticity and circuit activity. However, a recent overall view of the effects of muscarinic acetylcholine receptors (mAChRs) on excitatory and inhibitory long-term synaptic plasticity and on circuit activity is lacking. This review focusses on specific aspects of the regulation of synaptic plasticity and circuit activity by mAChRs in the hippocampus and cortex. Acetylcholine increases the excitability of pyramidal neurons, facilitating the generation of dendritic Ca²⁺-spikes, NMDA-spikes and action potential bursts which provide the main source of Ca²⁺ influx necessary to induce synaptic plasticity. The activation of mAChRs induced Ca²⁺ release from intracellular IP₃-sensitive stores is a major player in the induction of a NMDA independent long-term potentiation (LTP) caused by an increased expression of AMPA receptors in hippocampal pyramidal neuron dendritic spines. In the neocortex, activation of mAChRs also induces a long-term enhancement of excitatory postsynaptic currents. In addition to effects on excitatory synapses, a single brief activation of mAChRs together with short repeated membrane depolarization can induce a long-term enhancement of GABA A type (GABA_A) inhibition through an increased expression of GABA_A receptors in hippocampal pyramidal neurons. By contrast, a long term depression of GABA_A inhibition (iLTD) is induced by muscarinic receptor activation in the absence of postsynaptic depolarizations. This iLTD is caused by an endocannabinoid-mediated presynaptic inhibition that reduces the GABA release probability at the terminals of inhibitory interneurons. This bidirectional long-term plasticity of inhibition may dynamically regulate the excitatory/inhibitory balance depending on the quiescent or active state of the postsynaptic pyramidal neurons. Therefore, acetylcholine can induce varied effects on neuronal activity and circuit behavior that can enhance sensory detection and processing through the modification of circuit activity leading to learning, memory and behavior.