Muscarinic acetylcholine receptor-dependent persistent activity of layer 5 intrinsic-bursting and regular-spiking neurons in primary auditory cortex

Abstract

Cholinergic signaling coupled to sensory-driven neuronal depolarization is essential for modulating lasting changes in deep-layer neural excitability and experience-dependent plasticity in the primary auditory cortex. However, the underlying cellular mechanism(s) associated with coincident cholinergic receptor activation and neuronal depolarization of deep-layer cortical neurons remains unknown. Using in vitro whole cell patch-clamp recordings targeted to neurons (n = 151) in isolated brain slices containing the primary auditory cortex (AI), we investigated the effects of cholinergic receptor activation and neuronal depolarization on the electrophysiological properties of AI layer 5 intrinsic-bursting and regular-spiking neurons. Bath application of carbachol (5 μM; cholinergic receptor agonist) paired with suprathreshold intracellular depolarization led to persistent activity in these neurons. Persistent activity may involve similar cellular mechanisms and be generated intrinsically in both intrinsic-bursting and regular-spiking neurons given that it 1) persisted under the blockade of ionotropic glutamatergic (kynurenic acid, 2 mM) and GABAergic receptors (picrotoxin, 100 μM), 2) was fully blocked by both atropine (10 μM; nonselective muscarinic antagonist) and flufenamic acid [100 μM; nonspecific Ca2+-sensitive cationic channel (CAN) blocker], and 3) was sensitive to the voltage-gated Ca2+ channel blocker nifedipine (50 μM) and Ca2+-free artificial cerebrospinal fluid. Together, our results support a model through which coincident activation of AI layer 5 neuron muscarinic receptors and suprathreshold activation can lead to sustained changes in layer 5 excitability, providing new insight into the possible role of a calcium-CAN-dependent cholinergic mechanism of AI cortical plasticity. These findings also indicate that distinct streams of auditory processing in layer 5 intrinsic-bursting and regular-spiking neurons may run in parallel during learning-induced auditory plasticity. NEW & NOTEWORTHY Cholinergic signaling coupled to sensory-driven neuronal depolarization is essential for modulating lasting changes in experience-dependent plasticity in the primary auditory cortex. Cholinergic activation together with cellular depolarization can lead to persistent activity in both intrinsic-bursting and regular-spiking layer 5 pyramidal neurons. A similar mechanism involving muscarinic acetylcholine receptor, voltage-gated Ca2+ channel, and possible Ca2+-sensitive nonspecific cationic channel activation provides new insight into our understanding of the cellular mechanisms that govern learning-induced auditory cortical and subcortical plasticity.