Role of NMDA receptors in awake-state thalamocortical slow waves

描述（由申请人提供）：δ/θ频率范围内的大振幅、整体EEG振荡通常是慢波睡眠的特征。然而，在精神分裂症中，额叶和中央区在清醒时的δ功率很高。这被称为丘脑皮质节律障碍。精神分裂症的许多症状可以由NMDAR拮抗剂诱导;大鼠的研究表明，将NMDAR拮抗剂注射到丘脑中可以诱导δ频率节律障碍。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。我们的初步研究结果指出了一个细胞机制：丘脑网状核（nRT）的细胞被NMDAR拮抗剂超极化;这使T型Ca 2+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，在原位杂交显示，丘脑细胞含有一种罕见的形式的NMDAR亚基，NR 2C。该亚基在静息电位下被Mg 2+微弱阻断，因此响应于环境谷氨酸产生显著的内向电流;阻断该电流导致产生δ频率爆发的超极化。因此，我们的工作指出了心律失常的分子/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。我们的初步研究结果表明，D2的行动可能是协同与NMDA功能减退，在生产节律障碍。我们将在体内研究这一过程，以确定是否可以通过D2拮抗剂减少NMDA功能减退诱导的δ振荡。R. Llinas，是丘脑的子区域在相关的皮层子区域产生异常的低频振荡;这产生了信息处理的局部缺陷，这是疾病症状的基础。我们工作的最后一个目标是检验这个假设。我们将使用CRE重组酶方法在nRT的亚区中产生发育后敲除NMDAR。我们将测试前nRT中的NMDAR敲除是否可以在精神分裂症中受影响的额叶/中央区域产生δ功率的增强，而不影响枕叶皮质。我们将测试这些区域介导的行为是否选择性地受到这些振荡的影响。因为CRE重组酶方法产生慢性变化，它提供了一个模型系统，用于识别精神分裂症和药物治疗的慢性过程。如果成功，这种小鼠将模拟精神分裂症的EEG症状，并提供一个系统，在该系统中，可以根据丘脑的已知药理学来识别潜在的治疗靶点，然后测试它们逆转EEG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.