Muscarinic modulation of spike-timing dependent plasticity at recurrent layer 2/3 synapses in mouse auditory cortex

Cholinergic systems contribute to the refinement of auditory cortical receptive fields by activating muscarinic acetylcholine receptors (mAChRs). However, the specific cellular and synaptic mechanisms underlying acetylcholine9s effects on cortical circuits are not fully understood. In this study, we investigate the effects of muscarinic receptor modulation on spike-timing dependent plasticity (STDP) at synapses onto layer 2/3 pyramidal neurons in mouse auditory cortex (AC). Synapses onto layer 2/3 pyramidal neurons exhibit a STDP rule for pairing of postsynaptic spike bursts with single presynaptic stimuli. Pre-before-post pairing at +10 ms results in a timing-dependent long-term potentiation (tLTP), whereas pre-before-post pairing at +50 ms intervals, and post-before-pre pairing at -10 to -20 ms produce a timing-dependent long-term depression. We also characterize how mAChR activation affects plasticity at these synapses, focusing on the induction of tLTP. During pre-before-post pairing at +10 ms, mAChR activation by either carbachol or oxotremorine-M suppresses tLTP. mAChR activation also reduces the NMDA-receptor dependent synaptically evoked increase in calcium in dendrites, apparently without affecting presynaptic transmitter release. Pharmacological experiments suggest that M1 and M3 receptors are not involved in the mAChR-mediated suppression of tLTP. Taken together, these results suggest activating mAChRs in layer 2/3 intracortical circuits can modify the circuit dynamics of AC by depressing tLTP mediated by NMDA receptors, and depressing calcium influx at excitatory synapses onto layer 2/3 pyramidal cells.