Epilepsies are a diverse group of paroxysmal disorders that have been linked to genetic or acquired ion channel and/or neurotransmitter receptor dysfunctions, the so-called """"""""channelopathies."""""""" The hippocampal mossy fibers undergo molecular and structural rearrangement in human and experimental mesial temporal lobe epilepsy (MTLE). Recent data revealed a robust down-regulation of both group II metabotropic glutamate receptors (mGluR II) and the large conductance Ca2+activated potassium channel (BK channels) in mossy fibers of epileptic rats. In the normal brain, """"""""feedback"""""""" activation of presynaptic autoreceptor mGluR II in concert with other ion channels (i.e., BK channels) attenuates excessive excitatory transmission. Hence, presynaptic deficit in mGluR II and BK channels may play a major role in epileptogenesis.
The specific aims of this project are: (1) to test the hypothesis that down-regulation of mGluR II and BK channels in mossy fiber of epileptic rats correlates with similar deficit in mRNA transcripts and abnormal expression of splice variants in granule cells;(2) to test the hypothesis that seizure-induced down-regulation of mGluR II and BK channels affects presynaptic function and exacerbates excitatory transmission at mossy fiber-CA3 pyramidal cell synapses in an experimental MTLE;and (3) to determine whether mGluR II and BK channels can attenuate excessive excitatory transmission at newly """"""""recurrent"""""""" mossy fiber-granule cell synapses in a rat model of MTLE. A combination of modern techniques will be used to study presynaptic mechanisms in control versus chronically epileptic rats. Such approaches will include tissue and seizure monitoring, single-cell quantitative real-time PCR, visualized patch-clamp recordings from granule cells and direct visualization of the presynaptic function via the fluorescent styryl dye FM1-43. The long-term goal is to decipher the molecular mechanisms determining """"""""acquired presynaptic channelopathies"""""""" and to investigate the consequences of such presynaptic dysfunction in the pathogenesis of MTLE. Data from this proposal may provide the foundation for novel therapeutic interventions for epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Enhancement Award (SC1)
Project #
5SC1NS063950-04
Application #
7902011
Study Section
Special Emphasis Panel (ZGM1-MBRS-5 (SC))
Program Officer
Whittemore, Vicky R
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$232,769
Indirect Cost
Name
University/Texas Brownsville & Southmost Coll
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
800187965
City
Brownsville
State
TX
Country
United States
Zip Code
78520
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