Cholinergic inputs to cortical cholinergic neurons facilitate disinhibition of excitatory neurons in the rat cerebral cortex

[Speaker] Keisuke Kaneko:1
[Co-author] Sachie Matsumura:2, Yoshiyuki Oi:1, Masayuki Kobayashi:3
1:Department of Anesthesiology, Nihon University School of Dentistry, Japan, 2:Department of Pediatric Dentistry, Nihon University School of Dentistry, Japan, 3:Department of Pharmacology, Nihon University School of Dentistry, Japan

Recent studies have demonstrated that the cerebral cortex involves cholinergic interneurons in addition to projections of cholinergic inputs from the basal forebrain (BF). Cholinergic interneurons are vasoactive intestinal peptide (VIP)-positive and are distributed in layers 2/3 with a bipolar morphology. There is a report that these neurons do not exert direct postsynaptic response in neighboring neurons, but indirectly induce an increase in spontaneous EPSCs in adjacent pyramidal neurons and regulate local cortical function. Cortical VIP-positive interneurons are activated by cholinergic projection from BF, and project to the dendrites of somatostatin (SST)-positive neurons and parvalbumin (PV)-positive neurons, each of which inhibit adjacent pyramidal neurons. As a result, cholinergic inputs from BF disinhibit excitatory neurons by exerting VIP-positive neuron-induced suppression of SST/PV-positive neurons. However, less is known about the cellular mechanisms of neuromodulation by cholinergic interneurons in the cerebral cortex. Here, we performed whole-cell recording from cholinergic interneurons co-expressing VGAT-Venus and ChAT-tdTomato and other subtypes of neurons in the insular cortex (IC), and analyzed their morphology, electrophysiological membrane properties, postsynaptic responses, and cross-correlation. Cholinergic interneurons principally distributed in layers 2/3 and display double bouquet morphology. All of them were Venus-positive, suggesting that cortical cholinergic neurons are also GABAergic. These cholinergic neurons activated were depolarized and their inter event interval of miniature EPSCs was decreased by carbachol, suggesting that cholinergic inputs from the BF facilitate cholinergic interneuronal activities. We also found that cholinergic interneurons had gap-junctions among the same subtype of neurons, and the activation of these neurons increases the synchrony of spike firing, suggesting that these cholinergic interneurons are coordinately working on inhibition of GABAergic neurons. Moreover, cholinergic interneurons induced inhibitory postsynaptic currents in neighboring GABAergic interneurons, which were diminished by atropine, suggesting that co-released acetylcholine plays a role in facilitation of inhibition. These findings suggest that cholinergic neurons are likely to play a role in disinhibition of the activities of pyramidal neurons, which may be involved in the mechanisms for cholinergic inputs-induced excitation of cortical activities.
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