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

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.