Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.
Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.
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DOI：
10.1016/j.nbd.2023.106248
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发表时间：
2023-09
影响因子：
6.1
通讯作者：
Jacob, Tija C.
中科院分区：
文献类型：
--
作者：
Lorenz-Guertin, Joshua M.;Povysheva, Nadya;Chapman, Caitlyn A.;Macdonald, Matthew L.;Fazzari, Marco;Nigam, Aparna;Nuwer, Jessica L.;Das, Sabyasachi;Brady, Megan L.;Vajn, Katarina;Bambino, Matthew J.;Weintraub, Susan T.;Johnson, Jon W.;Jacob, Tija C.
苯二氮卓 (BZ) 药物通过增强含有 GABA A 型受体 (GABAAR) 的 γ2 亚基来治疗癫痫、焦虑、失眠和酒精戒断。 BZ 的临床使用受到耐受性和戒断症状的阻碍，包括癫痫易感性增加、恐慌和睡眠障碍。在这里，我们研究了对苯二氮卓类镇静耐受的小鼠的抑制性 GABA 能和兴奋性谷氨酸可塑性。重复地西泮 (DZP) 治疗可减弱镇静作用并降低 DZP 对 GABAAR 突触电流的增强作用，但不影响整体突触抑制。虽然 DZP 没有改变 γ2-GABAAR 亚基组成，但突触外 GABAAR 重新分配到突触，导致突触 BZ 不敏感的含 α4 GABAAR 水平更高，并伴随强直抑制的减少。相反，兴奋性谷氨酸突触传递增加，NMDAR 亚基在突触和总蛋白水平上调。定量蛋白质组学进一步揭示了关键促兴奋介质的皮层神经适应和 Ca2+/钙调蛋白依赖性蛋白激酶 II (CAMKII)、MAPK 和 PKC 信号传导所强调的突触可塑性途径。因此，抑制性 GABA 能张力的降低和谷氨酸能神经传递的升高会导致兴奋/抑制平衡的破坏，并降低 BZ 治疗能力和苯二氮卓类耐受性。
Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAAR subunit composition, there was a redistribution of extrasynaptic GABAARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABAARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.
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影响因子：
33.6
作者：
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影响因子：
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