Globus pallidus externus (GPe) is a nucleus in the indirect pathway of basal ganglia circuitry which was originally considered to be a group of homogenous GABAergic projection neurons producing downstream inhibition of subthalamic nuclei (STN). However, recent evidence using genetic reporter lines have revealed that there are three classes of neurons in this region which have different electrophysiology properties and different projections. These cell types include parvalbumin neurons, arkypallidal neurons and Lhx6 neurons. This knowledge has important implications for our basic understanding of GPe physiology and to the GPe dysfunction observed in movement disorders including Parkinson's disease and Huntington's disease. However, there remains a critical gap in our knowledge of glutamatergic system in GPe which can potentially be used to modulate dysfunctional basal ganglia circuitry. In particular the function of various NMDA receptor subtypes in the different classes of GPe neurons is unknown. We propose to address the expression and function of GluN2C/GluN2D subunits in GPe since these receptors have many unusual properties including lower sensitivity to Mg2+-block, higher glutamate/glycine affinity and lack of desensitization which are optimal for tonic activity observed in GPe neurons. Our preliminary data and previous reports suggest that GluN2C/GluN2D may express in a cell-specific manner in GPe. Therefore, activation of GluN2C/GluN2D receptors may produce unique changes in GPe function and downstream inhibition which may allow fine tuning of disrupted basal ganglia circuitry in movement disorders. We will address the functional expression of the GluN2C and/or GluN2D subunits in GPe in a cell-type specific manner and elucidate their roles in cellular excitability and inhibitory tone in STN and potential relevance to behavioral deficits and cortical oscillation abnormalities in Parkinson's disease. We will use a multidisciplinary approach involving electrophysiological and behavioral studies together with pharmacological and DREADD tools as well as genetic and reporter lines and parkinsonian mouse models to address our goals.

Public Health Relevance

Globus pallidus is a nucleus of the basal ganglia circuitry which regulates movement. Pathological changes in globus pallidus correlate with Parkinson's and Huntington's disease. Recent studies have greatly enhanced our understanding of the cell types in globus pallidus and their projections. We propose to assess the subtypes of NMDA class of ionotropic glutamate receptors expressed on these distinct cell types and their influence on neuronal activity. We will also address the impact of modulation these receptors on motor dysfunction in a mouse model of Parkinson's disease. This information is critical for identifying novel means to normalize dysfunctional circuits and treat symptoms in movement disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Sieber, Beth-Anne
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Creighton University
Schools of Medicine
United States
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Alsaad, Hassan A; DeKorver, Nicholas W; Mao, Zhihao et al. (2018) In the Telencephalon, GluN2C NMDA Receptor Subunit mRNA is Predominately Expressed in Glial Cells and GluN2D mRNA in Interneurons. Neurochem Res :
Liu, Jinxu; Gandhi, Pauravi J; Pavuluri, Ratnamala et al. (2018) Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens. Transl Psychiatry 8:219
Ravikrishnan, Aparna; Gandhi, Pauravi J; Shelkar, Gajanan P et al. (2018) Region-specific Expression of NMDA Receptor GluN2C Subunit in Parvalbumin-Positive Neurons and Astrocytes: Analysis of GluN2C Expression using a Novel Reporter Model. Neuroscience 380:49-62