5-HT3a Receptors Modulate Hippocampal Gamma Oscillations by Regulating Synchrony of Parvalbumin-Positive Interneurons.

Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders.

Involvement of reactive oxygen species in the immunosuppressive effect of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a food-born carcinogenic heterocyclic amine.

A heterocyclic amine, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the potent food-borne dietary carcinogens derived mainly from burnt meat products. In the present study, we investigated the immunosuppressive effect of Trp-P-1 on the blastogenesis of lymphocytes prepared from spleen and thymus of Balb/c mice. Trp-P-1 inhibited, in a dose-dependent manner, proliferation of splenocytes in response to a B-cell mitogen, lipopolysaccharide and of both splenocytes and thymocytes in response to T-cell mitogens, concanavalin A and phytohemagglutinin, or non-receptor-mediated stimuli, phobol 12-myristate 13-acetate/ionomycin. Interestingly, Trp-P-1-inhibited proliferation in the splenocytes was restored almost completely by N-acetyl-l-cysteine (NAC) and partially by glutathione (GSH), whereas no effect was found when superoxide dismutase and catalase were used. Moreover, Trp-P-1 enhanced the mitogen-induced NF-kappaB binding activity to its cognate binding sequences, which is known to be mediated by intracellular reactive oxygen species (ROS) generation. Collectively, these results suggest that the immunosuppressive effect of Trp-P-1 is mediated by suppressing blastogenesis of lymphocytes via intracellular generation of ROS sensitive to NAC and/or GSH.