The subthalamic nucleus (STN) is composed of glutamate-containing neurons that drive the output of the basal ganglia. Moreover, the bursting pattern of action potentials in STN neurons has been associated with symptoms of Parkinson's disease. However, there is much to be learned about physiological and pharmacological mechanisms that regulate the activity of STN neurons. Using standard whole-cell patch-clamp recording techniques in slices of rat brain, our preliminary data show that blocking of the ATP-sensitive K+ (K-ATP) channels significantly increases firing rate, prolongs depolarizing plateau potentials, and augments N-methyl-D-aspartate (NMDA)-induced burst firing in STN neurons. Moreover, we present data suggesting that NMDA receptor stimulation produces concomitant activation of K-ATP current by a nitric oxide- dependent mechanism. This effect of NMDA might be specific for STN neurons because NMDA does not evoke K-ATP currents in substantia nigra pars compacta dopamine neurons.
The aims of this grant application are to 1) define the receptor pharmacology of K-ATP currents in STN neurons, 2) characterize NMDA/K-ATP interactions on membrane properties, 3) identify second messenger systems that mediate NMDA activation of K-ATP currents, and 4) characterize the influence of K-ATP currents on excitability and firing patterns of STN neurons from normal rats as well as in a 6-hydroxydopamine rat model of Parkinson's disease. Our proposed studies will significantly increase our understanding of how STN neurons are regulated by NMDA receptor- gated and K-ATP currents. Results may also suggest new ways to pharmacologically modify STN neuronal activity that would benefit patients with Parkinson's disease.

Public Health Relevance

Many studies suggest that excessive burst firing in subthalamic nucleus (STN) neurons contributes to symptoms of Parkinson's disease. Our preliminary studies show that burst firing that is evoked by N-methyl-D-aspartate (NMDA) receptor stimulation can be inhibited by concomitant activation of inhibitory currents generated by ATP-sensitive K+ (K-ATP) channels. By better understanding the interplay between NMDA and K-ATP currents in the STN, our studies may lead to new pharmacological strategies for the treatment of Parkinson's disease symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038715-13
Application #
8269710
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
1999-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$270,113
Indirect Cost
$55,738
Name
Oregon Health and Science University
Department
Neurology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Shen, K-Z; Yakhnitsa, V; Munhall, A C et al. (2014) AMP kinase regulates K-ATP currents evoked by NMDA receptor stimulation in rat subthalamic nucleus neurons. Neuroscience 274:138-52
Shen, Ke-Zhong; Johnson, Steven W (2013) Group I mGluRs evoke K-ATP current by intracellular Ca2+ mobilization in rat subthalamus neurons. J Pharmacol Exp Ther 345:139-50
Shen, Ke-Zhong; Johnson, Steven W (2012) Regulation of polysynaptic subthalamonigral transmission by D2, D3 and D4 dopamine receptors in rat brain slices. J Physiol 590:2273-84
Shen, Ke-Zhong; Johnson, Steven W (2012) Gamma-aminobutyric acid(B) receptor activation suppresses stimulus-evoked burst firing in rat substantia nigra reticulata neurons. Neuroreport 23:40-4
Shen, Ke-Zhong; Johnson, Steven W (2010) Ca2+ influx through NMDA-gated channels activates ATP-sensitive K+ currents through a nitric oxide-cGMP pathway in subthalamic neurons. J Neurosci 30:1882-93
Paquette, Melanie A; Anderson, Akari M; Lewis, Jason R et al. (2010) MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism. Neuropharmacology 58:1002-8
Paquette, Melanie A; Foley, Katherine; Brudney, Elizabeth G et al. (2009) The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism. Psychopharmacology (Berl) 204:743-54
Paquette, Melanie A; Brudney, Elizabeth G; Putterman, Daniel B et al. (2008) Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias. Neuroreport 19:111-5
Shen, Ke-Zhong; Johnson, Steven W (2008) Complex EPSCs evoked in substantia nigra reticulata neurons are disrupted by repetitive stimulation of the subthalamic nucleus. Synapse 62:237-42
Shen, K-Z; Johnson, S W (2008) 5-HT inhibits synaptic transmission in rat subthalamic nucleus neurons in vitro. Neuroscience 151:1029-33

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