Molecular and functional diversity of NMDA receptors in the thalamus

大脑皮层和丘脑之间的交流对于在意识体验中整合思想、情感和感觉至关重要。皮质丘脑回路功能连接的改变破坏了丘脑兴奋和抑制的平衡，从而导致大脑中超同步活动的传播。这在癫痫、精神疾病和运动障碍中很常见，在这些疾病中，知觉、运动、情绪影响、认知和意识都可能受到干扰。皮层和丘脑通过相互的谷氨酸能皮质丘脑和丘脑皮质投射进行交流，这些投射将侧枝发送到gabaergic网状丘脑。网状神经元对丘脑皮质神经元提供局部前馈和反馈抑制。在神经系统疾病中，这种回路的不同方面出现了差错。获得对该回路内突触生理学的详细了解将促进我们对特定通路如何失调的理解，并确定通路特异性干预的假定目标。我们知道不同的谷氨酸能输入在丘脑中具有不同的突触传递模式，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（NMDARs）是对兴奋性突触传递至关重要的离子性谷氨酸受体。NMDARs在丘脑生理和病理生理中具有明确的功能。然而，NMDARs根据其GluN2亚基组成具有截然不同的功能特性。这四个

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.