Cellular Mechanism of Synchrony Impairments in Schizophrenia

摘要 在精神分裂症中经常观察到的伽玛范围内异常的神经元同步性可能与 认知缺陷。尽管有证据表明，以锥体细胞为靶点的皮质快速刺激性中间神经元 可能与神经元同步性有关，是精神分裂症神经元同步性异常的细胞基础 仍有待确认。我们最近证实，出生后早期大脑皮质中NMDA受体的缺失 而海马区的中间神经元，其中大部分是含有小白蛋白的，足以触发几个 类似人类精神分裂症的小鼠的病理生理学特征。这些突变的小鼠表现出几个 行为认知性缺陷和惊吓反射的脉冲前抑制。它们还显示出一种减弱的 皮质锥体细胞之间的棘波同步性与音调诱发伽马频率振荡的缺陷 通过活体记录测量听觉皮质局部场电位的活动。至关重要的是要描绘出 NMDA受体后突触后神经元同步放电损伤的机制 皮质中间神经元的消融。我们最近发现糖原合成酶激酶3(GSK3)表达上调- NMDAR缺失的快峰中间神经元的调节性和Cav2.1(P/Q型)通道电流减弱 突变的小鼠。此外，抑制GSK3活性可显著增加Cav2.1通道电流 改善体外同步释放GABA的缺陷。我们假设GSK3在 NMDA受体缺陷的快速放电中间神经元下调Cav2.1通道功能，从而损害 大脑皮质中GABA的同步释放和同步振荡导致认知功能障碍。这个 本应用的目的是确定NMDA中GSK3和Cav2.1通道的异常调节 受体缺失的快脉冲神经元对受损的同步GABA释放至关重要，以及 这些分子的功能恢复不仅挽救了体内异常的神经元同步性，而且还 行为认知功能障碍。拟议中的研究可能会对细胞机制产生新的见解。 皮质神经元的同步性，可能导致开发治疗认知功能障碍的新药 精神分裂症，这是目前医学上难以解决的问题。

Abstract Abnormal neuronal synchrony at gamma range, often observed in schizophrenia, may be associated with cognitive deficits. Although evidence suggests that cortical fast-spiking interneurons targeting pyramidal cells may be involved in neuronal synchrony, cellular basis of abnormal neuronal synchrony in schizophrenia remains to be identified. We recently demonstrated that early postnatal deletion of NMDA receptors in cortical and hippocampal interneurons, majority of which are parvalbumin containing, was sufficient to trigger several pathophysiological features in mice that resemble human schizophrenia. The mutant mice exhibit several behavioral cognitive-like deficits and prepulse inhibition of the startle reflex. They also display a diminished spike synchrony between cortical pyramidal cells and a deficit in tone-evoked gamma frequency oscillatory activity of local field potentials in auditory cortex, measured by in vivo recordings. It is crucial to delineate the underlying mechanisms of the synchronous firing impairment of postsynaptic neurons following NMDA receptor ablation in cortical interneurons. We recently discovered that glycogen synthase kinase 3 (GSK3) is up- regulated and Cav2.1 (P/Q-type) channel currents are diminished in NMDAR-deleted fast-spiking interneurons of the mutant mice. Furthermore, inhibition of GSK3 activity augmented Cav2.1 channel currents and largely ameliorates the deficit in synchronized GABA release ex vivo. We hypothesize that that GSK3 up-regulation in the NMDA receptor-deficient fast-spiking interneurons down-regulates Cav2.1 channel function, which impairs synchronized GABA release and synchronized oscillations in the cortex producing cognitive dysfunction. The objective of this application is to determine whether dysregulation of GSK3 and Cav2.1 channels in the NMDA receptor-deleted fast-spiking neurons is crucial for an impaired synchronized GABA release and whether functional restoration of these molecules rescues not only in vivo abnormal neuronal synchrony but also behavioral cognitive dysfunction. The proposed studies may yield new insights into cellular mechanisms of cortical neuronal synchrony, potentially leading to development of novel drugs for cognitive dysfunction of schizophrenics, which is currently medically intractable.