Cell-Type Specific Neuromodulation of Excitatory and Inhibitory Neurons via Muscarinic Acetylcholine Receptors in Layer 4 of Rat Barrel Cortex.

Guanxiao Qi,Dirk Feldmeyer

doi:10.3389/fncir.2022.843025

Abstract

The neuromodulator acetylcholine (ACh) plays an important role in arousal, attention, vigilance, learning and memory. ACh is released during different behavioural states and affects the brain microcircuit by regulating neuronal and synaptic properties. Here, we investigated how a low concentration of ACh (30 μM) affects the intrinsic properties of electrophysiologically and morphologically identified excitatory and inhibitory neurons in layer 4 (L4) of rat barrel cortex. ACh altered the membrane potential of L4 neurons in a heterogeneous manner. Nearly all L4 regular spiking (RS) excitatory neurons responded to bath-application of ACh with a M4 muscarinic ACh receptor-mediated hyperpolarisation. In contrast, in the majority of L4 fast spiking (FS) and non-fast spiking (nFS) interneurons 30 μM ACh induced a depolarisation while the remainder showed a hyperpolarisation or no response. The ACh-induced depolarisation of L4 FS interneurons was much weaker than that in L4 nFS interneurons. There was no clear difference in the response to ACh for three morphological subtypes of L4 FS interneurons. However, in four morpho-electrophysiological subtypes of L4 nFS interneurons, VIP+-like interneurons showed the strongest ACh-induced depolarisation; occasionally, even action potential firing was elicited. The ACh-induced depolarisation in L4 FS interneurons was exclusively mediated by M1 muscarinic ACh receptors; in L4 nFS interneurons it was mainly mediated by M1 and/or M3/5 muscarinic ACh receptors. In a subset of L4 nFS interneurons, a co-operative activation of muscarinic and nicotinic ACh receptors was also observed. The present study demonstrates that low-concentrations of ACh affect different L4 neuron types in a cell-type specific way. These effects result from a specific expression of different muscarinic and/or nicotinic ACh receptors on the somatodendritic compartments of L4 neurons. This suggests that even at low concentrations ACh may tune the excitability of L4 excitatory and inhibitory neurons and their synaptic microcircuits differentially depending on the behavioural state during which ACh is released.

Highlights

Normal brain function relies on the participation of diverse neuromodulators such as the acetylcholine (ACh), noradrenaline, dopamine, and serotonin
Three layer 4 (L4) neuron types can be differentiated by only three electrophysiological parameters, i.e., the maximum firing frequency, action potential (AP) half-width and the AHP amplitude (Figures 1B,C)
We found that TRO completely blocked the ACh-induced hyperpolarisation in L4 regular spiking (RS) excitatory neurons (Supplementary Figure 3A) while PIR completely blocked the ACh-induced depolarisation in L4 fast spiking (FS) interneurons (Supplementary Figure 3B)

Summary

Introduction

Normal brain function relies on the participation of diverse neuromodulators such as the acetylcholine (ACh), noradrenaline, dopamine, and serotonin. These neuromodulators are mainly released from different subcortical brain regions during different cognitive and behavioural states and affect neuronal microcircuits differently yet in a collaborative way. ACh effects are mediated by two different types of receptors, the G-protein-coupled muscarinic ACh receptors (mAChRs) and the ionotropic nicotinic ACh receptors (nAChRs). In the neocortex, both receptor types show layerspecific distributions and effects (Obermayer et al, 2017; Radnikow and Feldmeyer, 2018). A similar ACh effect was found in L6A corticocortical neurons (Yang et al, 2020)

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