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 #
3SC1NS063950-03S1
Application #
7900125
Study Section
Special Emphasis Panel (ZGM1-MBRS-5 (SC))
Program Officer
Fureman, Brandy E
Project Start
2007-08-01
Project End
2011-07-31
Budget Start
2009-08-20
Budget End
2011-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$222,076
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
Upreti, Chirag; Otero, Rafael; Partida, Carlos et al. (2012) Altered neurotransmitter release, vesicle recycling and presynaptic structure in the pilocarpine model of temporal lobe epilepsy. Brain 135:869-85
Scorza, C A; Araujo, B H S; Leite, L A et al. (2011) Morphological and electrophysiological properties of pyramidal-like neurons in the stratum oriens of Cornu ammonis 1 and Cornu ammonis 2 area of Proechimys. Neuroscience 177:252-68
Jürgensen, Sofia; Antonio, Leandro L; Mussi, Gabriela E A et al. (2011) Activation of D1/D5 dopamine receptors protects neurons from synapse dysfunction induced by amyloid-beta oligomers. J Biol Chem 286:3270-6
Pacheco Otalora, Luis F; Skinner, Frank; Oliveira, Mauro S et al. (2011) Chronic deficit in the expression of voltage-gated potassium channel Kv3.4 subunit in the hippocampus of pilocarpine-treated epileptic rats. Brain Res 1368:308-16
Garrido-Sanabria, Emilio R; Perez-Cordova, Miriam G; Colom, Luis V (2011) Differential expression of voltage-gated K+ currents in medial septum/diagonal band complex neurons exhibiting distinct firing phenotypes. Neurosci Res 70:361-9
Oliveira, Mauro Schneider; Pacheco, Luis Fernando; Mello, Carlos Fernando et al. (2011) Epileptiform activity in the limbic system. Front Biosci (Schol Ed) 3:565-93
Ermolinsky, Boris S; Skinner, Frank; Garcia, Ileana et al. (2011) Upregulation of STREX splice variant of the large conductance Ca2+-activated potassium (BK) channel in a rat model of mesial temporal lobe epilepsy. Neurosci Res 69:73-80
Oliveira, Mauro S; Skinner, Frank; Arshadmansab, Massoud F et al. (2010) Altered expression and function of small-conductance (SK) Ca(2+)-activated K+ channels in pilocarpine-treated epileptic rats. Brain Res 1348:187-99
Ermolinsky, Boris; Pacheco Otalora, Luis F; Arshadmansab, Massoud F et al. (2008) Differential changes in mGlu2 and mGlu3 gene expression following pilocarpine-induced status epilepticus: a comparative real-time PCR analysis. Brain Res 1226:173-80
Garrido-Sanabria, Emilio R; Otalora, Luis F Pacheco; Arshadmansab, Massoud F et al. (2008) Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats. Brain Res 1240:165-76