Division of Translational Toxicology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, 10 S. Pine Street, Suite 900, Baltimore, MD 21201, United States.
Biochem Pharmacol. 2011 Oct 15;82(8):842-51. doi: 10.1016/j.bcp.2011.06.004. Epub 2011 Jun 13.
CA1 stratum radiatum interneurons (SRIs) express α7 nicotinic receptors (nAChRs) and receive inputs from glutamatergic neurons/axons that express α3β4β2 nAChRs. To test the hypothesis that endogenously active α7 and/or α3β4β2 nAChRs control the excitability of CA1 SRIs in the rat hippocampus, we examined the effects of selective receptor antagonists on spontaneous fast current transients (CTs) recorded from these interneurons under cell-attached configuration. The frequency of CTs, which represent action potentials, increased in the absence of extracellular Mg(2+) and decreased in the presence of the α3β4β2 nAChR antagonist mecamylamine (3 μM) or the NMDA receptor antagonist APV (50 μM). However, it was unaffected by the α7 nAChR antagonist MLA (10 nM) or the AMPA receptor antagonist CNQX (10 μM). Thus, in addition to synaptically and tonically activated NMDA receptors, α3β4β2 nAChRs that are present on glutamatergic axons/neurons synapsing onto SRIs and are activated by basal levels of acetylcholine contribute to the maintenance of the excitability of these interneurons. Kynurenic acid (KYNA), an astrocyte-derived kynurenine metabolite whose levels are increased in the brains of patients with schizophrenia, also controls the excitability of SRIs. At high micromolar concentrations, KYNA, acting primarily as an NMDA receptor antagonist, decreased the CT frequency recorded from the interneurons. At 2 μM, KYNA reduced the CA1 SRI excitability via mechanisms independent of NMDA receptor block. KYNA-induced reduction of excitability of SRIs may contribute to sensory gating deficits that have been attributed to deficient hippocampal GABAergic transmission and high levels of KYNA in the brain of patients with schizophrenia.
CA1 辐射层中间神经元 (SRIs) 表达 α7 烟碱型乙酰胆碱受体 (nAChRs)，并接收表达 α3β4β2 nAChRs 的谷氨酸能神经元/轴突的输入。为了检验内源性激活的 α7 和/或 α3β4β2 nAChRs 是否控制大鼠海马 CA1 SRI 兴奋性的假设，我们在细胞附着构型下检查了选择性受体拮抗剂对这些中间神经元记录的自发快速电流瞬变 (CT) 的影响。代表动作电位的 CT 的频率在不存在细胞外 Mg(2+)的情况下增加，而在 α3β4β2 nAChR 拮抗剂美加明 (3 μM) 或 NMDA 受体拮抗剂 APV (50 μM) 的存在下减少。然而，它不受 α7 nAChR 拮抗剂 MLA (10 nM) 或 AMPA 受体拮抗剂 CNQX (10 μM) 的影响。因此，除了突触和紧张性激活的 NMDA 受体外，存在于与 SRI 突触的谷氨酸能轴突/神经元上并被基底水平乙酰胆碱激活的 α3β4β2 nAChR 有助于维持这些中间神经元的兴奋性。犬尿酸 (KYNA)，一种星形胶质细胞衍生的色氨酸代谢物，其水平在精神分裂症患者的大脑中增加，也控制 SRI 的兴奋性。在高微摩尔浓度下，KYNA 主要作为 NMDA 受体拮抗剂，降低从中间神经元记录的 CT 频率。在 2 μM 时，KYNA 通过独立于 NMDA 受体阻断的机制降低 CA1 SRI 兴奋性。KYNA 诱导的 SRI 兴奋性降低可能导致感觉门控缺陷，这归因于海马 GABA 能传递缺陷和精神分裂症患者大脑中 KYNA 水平升高。
