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

Abstract

16Cholinergic systems contribute to the refinement of auditory cortical receptive fields by 17 activating muscarinic acetylcholine receptors (mAChRs). However, the specific cellular and 18 synaptic mechanisms underlying acetylcholine's effects on cortical circuits are not fully 19 understood. In this study, we investigate the effects of muscarinic receptor modulation on 20 spike-timing dependent plasticity (STDP) at synapses onto layer 2/3 pyramidal neurons in 21 mouse auditory cortex (AC). Synapses onto layer 2/3 pyramidal neurons exhibit a STDP 22 rule for pairing of postsynaptic spike bursts with single presynaptic stimuli. Pre-before-post 23 pairing at +10 ms results in a timing-dependent long-term potentiation (tLTP), whereas pre-24 before-post pairing at +50 ms intervals, and post-before-pre pairing at -10 to -20 ms 25 produce a timing-dependent long-term depression. We also characterize how mAChR 26 activation affects plasticity at these synapses, focusing on the induction of tLTP. During pre-27 before-post pairing at +10 ms, mAChR activation by either carbachol or oxotremorine-M 28 suppresses tLTP. mAChR activation also reduces the NMDA-receptor dependent 29 synaptically evoked increase in calcium in dendrites, apparently without affecting 30 presynaptic transmitter release. Pharmacological experiments suggest that M1 and M3 31 receptors are not involved in the mAChR-mediated suppression of tLTP. Taken together, 32 these results suggest activating mAChRs in layer 2/3 intracortical circuits can modify the 33 circuit dynamics of AC by depressing tLTP mediated by NMDA receptors, and depressing 34 calcium influx at excitatory synapses onto layer 2/3 pyramidal cells. 35 36 Rao, Kratz and Manis