Molecular and functional diversity of NMDA receptors in the thalamus

大脑皮质和丘脑之间的交流对于在有意识的体验中整合思想、情绪和感觉至关重要。皮质丘脑回路中功能连接的改变扰乱了丘脑兴奋和抑制的平衡，从而导致超同步活动在整个大脑中传播。这在癫痫、精神疾病和运动障碍中很常见，在这些疾病中，感知、运动、情感、认知和意识可能会被破坏。皮质和丘脑通过相互的谷氨酸能皮质和丘脑皮质投射进行交流，这些投射将侧支发送到GABA能网状丘脑。网状神经元对丘脑皮质神经元具有局部前馈和反馈抑制作用。在神经系统疾病中，这种回路的不同方面出现了问题。对这一回路中突触生理的详细了解将促进我们对特定通路如何变得失调的理解，并确定通路特异性干预的假定靶点。我们知道不同的谷氨酸能输入在丘脑有不同的突触传递方式，但值得注意的是，我们不知道哪些谷氨酸受体亚型在这些基本连接中表达。N-甲基-D-天冬氨酸受体(NMDAR)是一种离子亲性谷氨酸受体，在兴奋性突触传递中起关键作用。NMDAR在丘脑生理学和病理生理学中具有广泛的功能。然而，NMDAR的功能特性因其GluN2亚单位组成的不同而有很大不同。四个 GluN2亚型GluN2a-2D在丘脑中以不同的基因表达模式表达，但GluN2亚型的具体作用尚不清楚。我们假设GluN2亚基在丘脑中产生不同的NMDAR功能，这将允许GluN2选择性调制来不同地调节丘脑电路功能。NMDAR在大脑中无处不在，也是必不可少的。因此，先进的NMDAR疾病疗法需要找到一种方法来限制NMDAR的调制，以选择细胞类型或电路。GluN2亚基多样性和NMDAR药理学的最新进展为克服这一障碍提供了机会。这项研究利用GluN2选择性药理学和分子工具，结合超分辨率显微镜、脑切片生理学和体外光遗传学：1)确定GluN2亚型的组织和输入特定功能，2)定义GluN2亚型如何影响兴奋性和抑制性信号整合，以及3)确定GluN2选择性调制如何改变丘脑振荡。这项研究的完成将通过揭示皮层-丘脑通讯的突触和细胞机制来解决一个关键的知识缺口。这项工作将确定GluN2选择性NMDAR调制是否足以控制丘脑回路功能，并为开发疾病特异性策略来调节皮质丘脑回路中的选择通路奠定基础。

Communication between the cortex and thalamus is essential for integrating thoughts, emotions, and sensations in conscious experiences. Altered functional connectivity in corticothalamic circuits disrupts the balance of excitation and inhibition in the thalamus, which leads to propagation of hypersynchronous activity across the brain. This is common in epilepsy, psychiatric diseases, and movement disorders, in which perception, movement, emotional affect, cognition, and consciousness can be disrupted. The cortex and thalamus communicate via reciprocal glutamatergic corticothalamic and thalamocortical projections, which send collaterals to the gabaergic reticular thalamus. Reticular neurons provide local feed-forward and feedback inhibition to thalamocortical neurons. Distinct aspects of this circuitry go awry in neurological diseases. Gaining a detailed understanding of the synaptic physiology within this circuit will advance our understanding of how particular pathways become dysregulated and identify putative targets for pathway-specific interventions. We know that distinct glutamatergic inputs have diverse modes of synaptic transmission in the thalamus, but remarkably, we do not know which glutamate receptor subtypes are expressed at these essential connections. N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors critical for excitatory synaptic transmission. NMDARs have well-established functions in thalamic physiology and pathophysiology. However, NMDARs have vastly different functional properties depending on their GluN2 subunit composition. The four GluN2 subtypes, GluN2A-2D, are expressed in the thalamus with distinct gene expression patterns, but the specific roles of GluN2 subtypes are unknown. We hypothesize that GluN2 subunits give rise to diverse NMDAR functions in the thalamus that will allow GluN2-selective modulation to differentially tune thalamic circuit function. NMDARs are ubiquitous and essential in the brain. Therefore, advancing NMDAR disease therapies requires finding a way to limit NMDAR modulation to select cell types or circuits. GluN2 subunit diversity and recent advances in NMDAR pharmacology provide an opportunity to overcome this obstacle. This research utilizes GluN2-selective pharmacological and molecular tools with super-resolution microscopy, brain slice physiology, and ex vivo optogenetics to: 1) identify the organization and input-specific functions of GluN2 subtypes, 2) define how GluN2 subtypes impact excitatory and inhibitory signal integration, and 3) determine how GluN2-selective modulation alters thalamic oscillations. Completion of this research will address a critical knowledge gap by revealing synaptic and cellular mechanisms underlying corticothalamic communication. This work will determine if GluN2-selective NMDAR modulation is sufficient to control thalamic circuit function and form the foundation for developing disease-specific strategies to modulate select pathways in corticothalamic circuits.