Center for Neuroscience Research, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh, PA, USA.
Neurobiol Dis. 2010 Jun;38(3):464-75. doi: 10.1016/j.nbd.2010.03.012. Epub 2010 Mar 18.
Traumatic brain injury (TBI) can result in altered inhibitory neurotransmission, hippocampal dysfunction, and cognitive impairments. GABAergic spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and tonic (extrasynaptic) whole cell currents were recorded in control rat hippocampal dentate granule cells (DGCs) and at 90days after controlled cortical impact (CCI). At 34 degrees C, in CCI DGCs, sIPSC frequency and amplitude were unchanged, whereas mIPSC frequency was decreased (3.10+/-0.84Hz, n=16, and 2.44+/-0.67Hz, n=7, p<0.05). At 23 degrees C, 300nM diazepam increased peak amplitude of mIPSCs in control and CCI DGCs, but the increase was 20% higher in control (26.81+/-2.2pA and 42.60+/-1.22pA, n=9, p=0.031) compared to CCI DGCs (33.46+/-2.98pA and 46.13+/-1.09pA, n=10, p=0.047). At 34 degrees C, diazepam did not prolong decay time constants (6.59+/-0.12ms and 6.62+/-0.98ms, n=9, p=0.12), the latter suggesting that CCI resulted in benzodiazepine-insensitive pharmacology in synaptic GABA(A) receptors (GABA(A)Rs). In CCI DGCs, peak amplitude of mIPSCs was inhibited by 100microM furosemide (51.30+/-0.80pA at baseline and 43.50+/-5.30pA after furosemide, n=5, p<0.001), a noncompetitive antagonist of GABA(A)Rs with an enhanced affinity to alpha4 subunit-containing receptors. Potentiation of tonic current by the GABA(A)R delta subunit-preferring competitive agonist THIP (1 and 3microM) was increased in CCI DGCs (47% and 198%) compared to control DGCs (13% and 162%), suggesting the presence of larger tonic current in CCI DGCs; THIP (1microM) had no effect on mIPSCs. Taken together, these results demonstrate alterations in synaptic and extrasynaptic GABA(A)Rs in DGCs following CCI.
创伤性脑损伤 (TBI) 可导致抑制性神经递质传递改变、海马功能障碍和认知障碍。在对照大鼠海马齿状回颗粒细胞 (DGC) 和皮质撞击伤 (CCI) 后 90 天，记录 GABA 能自发性和微小抑制性突触后电流 (sIPSCs 和 mIPSCs) 和紧张性 (突触外) 全细胞电流。在 34°C 时，CCI DGCs 中的 sIPSC 频率和幅度不变，而 mIPSC 频率降低 (3.10+/-0.84Hz，n=16 和 2.44+/-0.67Hz，n=7，p<0.05)。在 23°C 时，300nM 地西泮增加对照和 CCI DGCs 中 mIPSCs 的峰值幅度，但对照 DGCs 的增加幅度高于 CCI DGCs (26.81+/-2.2pA 和 42.60+/-1.22pA，n=9，p=0.031)。在 34°C 时，地西泮没有延长衰减时间常数 (6.59+/-0.12ms 和 6.62+/-0.98ms，n=9，p=0.12)，后者表明 CCI 导致突触 GABA(A) 受体 (GABA(A)Rs) 中苯二氮䓬不敏感的药理学。在 CCI DGCs 中，mIPSCs 的峰值幅度被 100μM 速尿抑制 (基础值为 51.30+/-0.80pA，速尿后为 43.50+/-5.30pA，n=5，p<0.001)，速尿是 GABA(A)Rs 的非竞争性拮抗剂，对含有 alpha4 亚基的受体具有增强的亲和力。THIP (1 和 3μM)，一种 GABA(A)R δ 亚基优先竞争激动剂，增强 CCI DGCs 中紧张性电流的作用 (47%和 198%)，与对照 DGCs 相比 (13%和 162%)，提示 CCI DGCs 中存在较大的紧张性电流；THIP (1μM)对 mIPSCs 没有影响。总之，这些结果表明 CCI 后 DGCs 中突触和突触外 GABA(A)Rs 发生改变。
