Both 5-HT1A and 5-HT1B receptor-mediated inhibition of glutamatergic transmission onto cholinergic neurons in basal forebrain

[Speaker] Takuma Nishijo:1
[Co-author] Toshihiko Momiyama:1
1:Department of Pharmacology, Jikei University School of Medicine, Japan

Basal forebrain (BF) is an origin of cholinergic neurons which project to various brain regions including cortex and hippocampus. BF has been shown to be involved in attention, arousal, learning, and memory, as well as the related disorders, including dementia and Alzheimer's disease. Serotonin (5-HT) is a neuromodulator originating in the dorsal raphe nuclei and serotonergic fibers project and innervate various brain areas including BF nuclei. However, 5-HT-induced modulatory effects on the excitatory synaptic transmission in the BF are unknown. Therefore, this study was aimed to elucidate 5-HT-induced modulation of glutamatergic synaptic transmission onto cholinergic neurons in the BF. BF cholinergic neurons were identified with Cy3-192IgG injected into lateral ventricles at P8-9 and investigated in P12-20 rat brain slices using whole-cell patch-clamp technique. Pharmacologically isolated excitatory postsynaptic currents (EPSCs) were evoked by focal electrical stimulation. Bath application of 5-HT inhibited the amplitude of the evoked EPSCs. A 5-HT1A receptor agonist, (R)-(+)-8-OH-DPAT, or a 5-HT1B receptor agonist, CP93129, both inhibited the amplitude of EPSCs. A 5-HT1A receptor antagonist, NAN-190, or a 5-HT1B receptor antagonist, NAS-181, partially antagonized 5-HT-induced inhibition of EPSCs. In the presence of both antagonists, most of 5-HT-induced effect disappeared. 5-HT could still inhibit the EPSCs in the presence of ω-conotoxin GVIA, whereas 5-HT-induced inhibition was significantly smaller in the presence of ω-agatoxin TK than that without ω-agatoxin TK. While 5-HT had no significantly effect on paired-pulse ratio, 5-HT reduced synaptic strength by changing AMPA/NMDA ratio. These results suggest that 5-HT inhibits glutamatergic transmission onto BF cholinergic neurons and that both 5-HT1A and 5-HT1B receptors contribute to 5-HT-induced inhibition. They also suggest that 5-HT inhibits glutamatergic transmission by selectively blocking P/Q-type Ca2+ channels via pre- and postsynaptic mechanisms.
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