BACKGROUND AND AIMS: Damage to the cholinergic input to the prefrontal cortex has been implicated in neuropsychiatric disorders. Cholinergic endings release acetylcholine, which activates nicotinic and/or muscarinic receptors and regulates the membrane potential in medial prefrontal cortex (mPFC) neurons. The aim of this study was to clarify the mechanism responsible for control of the medial prefrontal cortex (mPFC) pyramidal neurons by muscarinic receptors. MATERIAL AND METHODS: Experiments were performed on mPFC pyramidal neurons in slices isolated from young (18–22- day-old) male rats. Recordings of membrane potential were performed with the gramicidin perforated-patch method in the absence of Ca2+ ions and in the presence of tetrodotoxin (TTX, 1 μM) in extracellular solution. RESULTS: Cholinergic receptor stimulation by carbamoylcholine chloride (CCh; 100 μM) evoked depolarization (10.0±1.3 mV), which was blocked by the M1/M4 (pirenzepine dihydrochloride, 2 μM) and M1 (VU 0255035, 5 μM) muscarinic receptor antagonists and was not affected by a nicotinic receptor antagonist (mecamylamine hydrochloride, 10 μM). CCh-dependent depolarization was greatly attenuated in the presence of an inhibitor of the βγ-subunitdependent transduction system (gallein, 20 μM). mPFC pyramidal neurons express Nav1.9 channels. CCh-dependent depolarization was abolished in the presence of antibodies against Nav1.9 channels in the intracellular solution and augmented by ProTx-I toxin (100 nM) in the extracellular solution. CONCLUSION: Activation of M1 muscarinic receptors evokes depolarization of mPFC pyramidal neurons due to activation of Nav 1.9-like Na+ channels via G-protein βγ-subunits (in a membranedelimited mode). The study was supported by NCN grants no: NN401584638, NN301572940 and WUM grant no: FW5/PM31D/14.
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