Role of NMDA receptors in awake-state thalamocortical slow waves

描述（由申请人提供）：在δ / θ频率范围内的大幅度，全局脑电图振荡通常是慢波睡眠的特征。然而，精神分裂症患者在清醒时，额叶和中央区域的δ能量很高。这被称为丘脑皮质性心律失常。NMDAR拮抗剂可诱发精神分裂症的许多症状；在大鼠身上的研究表明，向丘脑注射NMDAR拮抗剂可以诱发δ频率心律失常。我们工作的第一个目标是了解NMDAR拮抗剂如何产生这种异常。我们的初步结果指出了一种细胞机制：NMDAR拮抗剂使丘脑网状核（nRT）细胞超极化；这会使t型Ca2+通道失活，然后产生δ频率爆发。我们的第二个目标是了解这种效应的分子机制。我们的初步结果证实了原位杂交显示丘脑细胞含有一种罕见形式的NMDAR亚基NR2C。该亚基在静息电位下被Mg2+微弱阻断，因此在谷氨酸环境下产生显著的内向电流；这种电流的阻断会导致产生δ频率爆炸的超极化。因此，我们的工作指向心律失常的分子/细胞机制。我们工作的第三个目标是了解多巴胺如何与这些过程相互作用。我们的初步结果表明，D2的作用可能与NMDA功能低下协同产生心律失常。我们将在体内研究这一过程，以确定D2拮抗剂是否可以减少NMDA功能低下引起的delta振荡。R. Llinas提出的心律失常假说的一个关键方面是，丘脑的亚区在皮层的相关亚区产生异常的低频振荡；这就造成了局部信息处理缺陷，而这正是这种疾病症状的基础。我们工作的最终目标是验证这一假设。我们将使用CRE-recombinase方法在nRT的亚区产生NMDARs的发育后敲除。我们将测试NMDAR在前部nRT中的敲除是否会在精神分裂症患者的额叶/中央区域产生delta功率增强，而不影响枕叶皮层。我们将测试由这些区域介导的行为是否有选择地受到这些振荡的影响。由于CRE-重组酶方法产生慢性变化，它为识别精神分裂症和药物治疗背后的慢性过程提供了一个模型系统。如果成功，这只小鼠将模拟精神分裂症的脑电图症状，并提供一个系统，根据已知的丘脑药理学，可以确定潜在的治疗靶点，然后测试它们逆转脑电图症状的能力。

DESCRIPTION (provided by applicant): Large amplitude, global EEG oscillations in the delta/theta frequency range are normally characteristic of slow-wave sleep. In schizophrenia, however, delta power is high during wakefulness in frontal and central regions. This has been termed a thalamocortical dysrhythmia. Many symptoms of schizophrenia can be induced by NMDAR antagonists; work in rats shows that a delta frequency dysrhythmia can be induced by injection of NMDAR antagonist into the thalamus. The first goal of our work is to understand how NMDAR antagonists generate this abnormality. Our preliminary results point to a cellular mechanism: cells of the nucleus reticularis (nRT) of the thalamus are hyperpolarized by NMDAR antagonist; this deinactivates T-type Ca2+ channels which then generate delta frequency bursting. Our second goal is to understand the molecular mechanism of this effect. Our preliminary results confirm in situ hybridization showing that thalamic cells contain a rare form of NMDAR subunit, NR2C. This subunit is weakly blocked by Mg2+ at resting potential and thus generates a significant inward current in response to ambient glutamate; block of this current leads to the hyperpolarization that produces delta- frequency bursting. Thus our work points to a molecular/cellular mechanism for dysrhythmia. The third goal of our work is to understand how dopamine interacts with these processes. Our preliminary results suggest that D2 action may be synergistic with NMDA hypofunction in producing dysrhythmia. We will study this process in vivo to determine whether the delta oscillations induced by NMDA hypofunction can be reduced by D2 antagonist. A critical aspect of the dysrhythmia hypothesis, as proposed by R. Llinas, is that subregions of the thalamus generate abnormal low frequency oscillations in associated subregions of cortex; this produces local deficits in information processing that underlie the symptoms of the disease. A final goal of our work is to test this hypothesis. We will use a CRE-recombinase method to produce postdevelopmental knockout of NMDARs in subregions of the nRT. We will test whether NMDAR knockout in anterior nRT can produce enhancement of delta power in the frontal/central regions affected in schizophrenia, without affecting occipital cortex. We will test whether behaviors mediated by these regions are selectively affected by these oscillations. Because the CRE- recombinase method produces chronic changes, it provides a model system for identifying the chronic processes that underlie schizophrenia and drug therapy. If successful, this mouse will model the EEG symptoms of schizophrenia and provide a system in which potential therapeutic targets can be identified, based on the known pharmacology of the thalamus, and then tested for their ability to reverse the EEG symptoms.