Cell Type- and Layer-Specific Muscarinic Potentiation of Excitatory Synaptic Drive onto Parvalbumin Neurons in Mouse Prefrontal Cortex.

Tatiana B Tikhonova,Takeaki Miyamae,David A Lewis,Yelena Gulchina,Guillermo Gonzalez-Burgos

doi:10.1523/eneuro.0208-18.2018

Abstract

Cholinergic neuromodulation is thought to shape network activity in the PFC, and thus PFC-dependent cognitive functions. ACh may modulate the activity of parvalbumin-positive (PV+) neurons, which critically regulate cortical network function. However, the mechanisms of cholinergic regulation of PV+ neuron activity, and particularly of the basket cell (BC) versus chandelier cell (ChC) subtypes, are unclear. Using patch clamp recordings in acute slices, we examined the effects of the ACh receptor (AChR) agonist carbachol on the excitatory synaptic drive onto BCs or ChCs in layers 2 to 6 of mouse PFC. Carbachol increased the frequency and amplitude of spontaneous EPSCs (sEPSCs) recorded from PV+ BCs in layers 3-6, but not in BCs from layer 2. Moreover, carbachol did not change the sEPSCs in ChCs, which were located exclusively in layer 2. The potentiation of sEPSCs in layers 3-6 BCs was prevented by the Na+ channel blocker tetrodotoxin and was abolished by the M1-selective muscarinic AChR antagonist pirenzepine. Thus, carbachol potentiates the activity-dependent excitatory drive onto PV+ neurons via M1-muscarinic AChR activation in a cell type- and layer-specific manner. In current clamp recordings with synaptic transmission blocked, carbachol directly evoked firing in deep layer pyramidal neurons (PNs). In contrast, carbachol elicited deep layer BC firing indirectly, via glutamate-mediated synaptic drive. Our data suggest that ACh powerfully regulates PFC microcircuit function by facilitating the firing of PNs that synaptically recruit deep layer PV+ BC activity, possibly shaping the patterns of network activity that contribute to cognitive function.

Highlights

Regulation of cortical network activity by ACh plays a crucial role in cognitive function (Ballinger et al, 2016)
Consistent with previous findings that stimulation of M1 mAChRs facilitates deep layer pyramidal neurons (PNs) firing (Carr and Surmeier, 2007), we found that carbachol increased the excitatory drive onto PVϩ neurons in layers 3-6, via an effect prevented by an M1-selective mAChR antagonist or by tetrodotoxin, a Naϩ channel blocker that inhibits action potential firing
Previous studies of mouse PFC showed that ACh receptor (AChR) stimulation facilitates PN firing (Dembrow et al, 2010; Obermayer et al, 2017; Baker et al, 2018; Radnikow and Feldmeyer, 2018), an effect that may enhance the excitatory synaptic drive onto PVϩ cells

Summary

Introduction

Regulation of cortical network activity by ACh plays a crucial role in cognitive function (Ballinger et al, 2016). ACh depletion in the PFC (Croxson et al, 2011), or intra-PFC infusion of ACh receptor (AChR) antagonists (Howe et al, 2017), disrupt performance in cognitive tasks. Despite this crucial role of ACh, the mechanisms of cholinergic modulation of PFC network activity remain poorly understood. Many of the ACh effects on PNs, such as the excitatory mAChR response (McCormick and Prince, 1986; Gulledge et al, 2009), are layer dependent, being stronger in deep layers (Obermayer et al, 2017; Radnikow and Feldmeyer, 2018). Deep layer PNs show stronger nicotinic AChR-mediated responses (Poorthuis et al, 2013; Hedrick and Waters, 2015), which may be dependent on cortical region (Hedrick and Waters, 2015)

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Conclusion