Cellular Mechanism of Synchrony Impairments in Schizophrenia

摘要 神经元在γ范围内的异常同步，经常在精神分裂症中观察到，可能与 认知缺陷虽然有证据表明，皮质快速尖峰中间神经元针对锥体细胞， 可能参与神经元的同步性，精神分裂症神经元同步性异常的细胞基础 仍有待确认。我们最近发现，出生后早期大脑皮层NMDA受体缺失， 和海马中间神经元，其中大部分是含有小白蛋白，足以触发几个 小鼠的病理生理学特征类似于人类精神分裂症。突变小鼠表现出几种 行为认知类缺陷和惊吓反射的前脉冲抑制。他们也表现出一种减弱的 皮层锥体细胞间锋电位同步性与音调诱发γ频率振荡的缺陷 听觉皮层中的局部场电位的活动，通过体内记录测量。至关重要的是， NMDA受体介导突触后神经元同步放电障碍的机制 皮层中间神经元的消融。我们最近发现，糖原合成酶激酶3（GSK 3）是上调的- 在NMDAR缺失的快速尖峰中间神经元中，调节和Cav2.1（P/Q型）通道电流减少 突变小鼠的基因。此外，GSK3活性的抑制增强了Cav2.1通道电流， 改善离体同步GABA释放的缺陷。我们推测，GSK3的上调可能是由于GSK3的过度表达。 NMDA受体缺陷的快速尖峰中间神经元下调Cav2.1通道功能， 同步的GABA释放和皮层中的同步振荡产生认知功能障碍。的 本申请的目的是确定NMDA中GSK 3和Cav2.1通道的失调是否 受体缺失的快速尖峰神经元对受损的同步GABA释放至关重要， 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， 行为认知功能障碍这些研究可能会对细胞机制产生新的见解。 皮质神经元同步，可能导致开发用于认知功能障碍的新药， 精神分裂症，这是目前医学上棘手的。

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.