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INTRINSIC CURRENTS MODULATE SYNAPTIC INTEGRATION IN DOPAMINE NEURONS

Award Number: R01NS061097
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2009
PERIOD OF PERFORMANCE END DATE: 12/31/2014

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INTRINSIC CURRENTS MODULATE SYNAPTIC INTEGRATION IN DOPAMINE NEURONS - Abstract The overall objective is to characterize the contribution of the intrinsic properties of dopamine neurons to syn- aptic integration. Specifically, we will determine whether modulation of the ether-a-go-go-related gene (ERG) and/or the small conductance calcium-activated (SK) potassium channels alters their response to excitatory synaptic input. Bursts in dopamine neurons are thought to convey the reward prediction and salience signals. Schizophrenia is thought to result from disordered dopaminergic signaling. Antipsychotics attenuate the disor- dered dopaminergic signal, relieving psychosis, and usually partially block the K+ ERG current. The SK current masks background burst firing in dopamine neurons, and we propose the ERG K+ current as an additional, novel intrinsic component of burst firing. The specific hypotheses to be tested in this application are that: 1) the level of spontaneous bursting activity determines the ability of excitatory afferent inputs to trigger time-locked bursting activity and 2) that ERG K+ current in DA neurons provides a safeguard from depolarization block, and by extension ensures that synaptically driven increases in DA cell excitability are encoded and propagated to DA targets. "Depolarization block", a persistent depolarization in which action potentials are no longer sus- tained due to persistent sodium channel inactivation, is hypothesized to occur when the inward currents that promote bursting activity dominate the outward currents that attenuate it. A decrease in SK current is pre- dicted to facilitate both spontaneous and afferent-driven bursting, and in the presence of reduced ERG K+ cur- rent, to induce depolarization block. The specific aims are to test the predictions that 1) functional ERG K+ channels are expressed in dopamine neurons, 2) a reduction in SK current facilitates simulated spontaneous and synaptically-driven bursting activity in vitro, and that this bursting activity results to depolarization block unless relieved by the ERG K+ current, and 3) modulation of SK and/or ERG currents in DA neurons alters their ability to produce both spontaneous bursts as well as bursts in response to excitatory synaptic input in vivo. Electrophysiological recordings in rat brain combined with both complex multi-compartmental and simple neural models will be utilized in concert with experiments conducted with selective pharmacological agents to titrate the contribution of these currents to dopaminergic signaling. The modeling component is required to un- derstand the mechanisms underlying the generation of both types of bursting because of the complexity of the oscillatory mechanisms and the interactions between different regions of the dopaminergic neuron that likely function as coupled oscillators. The collective activity of the system is likely to have fundamentally different dy- namics in vivo compared to in vitro because of the interaction of intrinsic and synaptic mechanisms. A better understanding of how the firing pattern of DA neurons is regulated could result in the development of novel therapeutic targets for treating a variety of DA related disorders including Parkinson's disease, schizophrenia, drug and alcohol abuse.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $327,134 )
2013	2013	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/21/2013	NON-COMPETING CONTINUATION	$22,033
2013	2013	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/20/2012	NON-COMPETING CONTINUATION	$305,101
														Subtotal = $327,134

Issue Date FY: 2012 ( Subtotal = $340,678 )
2012	2012	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/1/2011	NON-COMPETING CONTINUATION	$312,525
2012	2012	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/3/2012	NON-COMPETING CONTINUATION	$28,153
														Subtotal = $340,678

Issue Date FY: 2011 ( Subtotal = $342,512 )
2011	2011	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/26/2010	NON-COMPETING CONTINUATION	$320,387
2011	2011	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/27/2011	NON-COMPETING CONTINUATION	$22,125
														Subtotal = $342,512

Issue Date FY: 2010 ( Subtotal = $344,399 )
2010	2010	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/20/2010	NON-COMPETING CONTINUATION	$31,308
2010	2010	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/4/2009	NON-COMPETING CONTINUATION	$313,091
														Subtotal = $344,399

Issue Date FY: 2009 ( Subtotal = $361,006 )
2009	2009	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/23/2008	NEW	$361,006
														Subtotal = $361,006

Grand Total All Awards = $1,715,729

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INTRINSIC CURRENTS MODULATE SYNAPTIC INTEGRATION IN DOPAMINE NEURONS

Award Number: R01NS061097

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2009

PERIOD OF PERFORMANCE END DATE: 12/31/2014

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