GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.
GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.
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DOI：
10.1038/tp.2012.69
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发表时间：
2012-07-17
影响因子：
6.8
通讯作者：
Siegel SJ
中科院分区：
文献类型：
--
作者：
Gandal MJ;Sisti J;Klook K;Ortinski PI;Leitman V;Liang Y;Thieu T;Anderson R;Pierce RC;Jonak G;Gur RE;Carlson G;Siegel SJ
N-甲基-D-天冬氨酸受体 (NMDAR) 信号传导减少与精神分裂症、自闭症和智力障碍有关。 NMDAR 功能减退被认为会导致社交、认知和伽马 (30–80Hz) 振荡异常，这是这些疾病的常见表型。然而，这种缺陷背后的电路级机制仍不清楚。本研究调查了 NMDA-NR1neo−/− 小鼠的 γ 同步性、兴奋性抑制 (E/I) 信号传导和行为表型之间的关系，这些小鼠已经组成性地减少了专性 NR1 亚基的表达，以模拟发育性 NMDAR 功能的破坏。组成性 NMDAR 功能减退导致 E/I 平衡丧失，锥体细胞内在兴奋性增加，选择性破坏表达小白蛋白的中间神经元。 E/I 耦合中断与听觉诱发的伽玛信噪比 (SNR) 缺陷相关。伽马带异常可预测空间工作记忆和社会偏好的缺陷，将 E/I 信号的细胞变化与目标行为联系起来。 GABAB 受体激动剂巴氯芬改善了 E/I 平衡、γ-SNR 并广泛逆转了行为缺陷。这些数据证明了一种临床相关的、高度可翻译的基于神经活动的生物标志物，可用于临床前筛选和治疗开发，适用于具有共同内表型和破坏的 NMDA 受体信号传导的广泛疾病。
Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.
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影响因子：
3.3
作者：
Ehrlichman, R. S.;Gandal, M. J.;Siegel, S. J.
通讯作者：
Siegel, S. J.
影响因子：
4.4
作者：
Connolly, PM;Maxwell, C;Siegel, SJ
通讯作者：
Siegel, SJ
影响因子：
3.3
作者：
Gandal, M. J.;Ehrlichman, R. S.;Siegel, S. J.
通讯作者：
Siegel, S. J.
影响因子：
10.6
作者：
Gandal, Michael J.;Edgar, J. Christopher;Ehrlichman, Richard S.;Mehta, Mili;Roberts, Timothy P. L.;Siegel, Steven J.
通讯作者：
Siegel, Steven J.
影响因子：
10.6
作者：
Buchanan, Robert W.;Keefe, Richard S. E.;Lieberman, Jeffrey A.;Barch, Deanna M.;Csernansky, John G.;Goff, Donald C.;Gold, James M.;Green, Michael F.;Jarskog, L. Fredrik;Javitt, Daniel C.;Kimhy, David;Kraus, Michael S.;McEvoy, Joseph P.;Mesholam-Gately, Raquelle I.;Seidman, Larry J.;Ball, M. Patricia;McMahon, Robert P.;Kern, Robert S.;Robinson, James;Marder, Stephen R.
通讯作者：
Marder, Stephen R.