Molecular and functional diversity of NMDA receptors in the thalamus

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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.