Temporal lobe epilepsy (TLE) is the most common form of epilepsy &is often medically intractable. A large body of evidence indicates that abnormalities in inhibitory neurotransmission play an important role in TLE. GABAA receptors (GABARs) are pentamers composed of subunits from multiple subunit families that display developmental, regional and disease specific differences in expression, however, little is known regarding their regulation either in health or in disease. Our laboratories have identified long-term changes in GABAR a subunit gene expression, including decreases in expression of the a1 gene (Gabra1) in rat hippocampal dentate granule neurons following status epilepticus (SE) that are associated with later development of epilepsy. In the previous funding period, we established that decreased transcription of Gabra1 after SE is mediated by inducible cAMP early repressor (ICER) and phosphorylated CREB that bind to the Gabra1 CRE site. We further showed that ICER transcription is activated by the Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling cascade, via actions of brain derived neurotrophic factor (BDNF). The JAK/STAT pathway has been little studied in epilepsy, and beyond its role in Gabra1 regulation, it is known to be an important regulator of neuronal proliferation, survival and gliogenesis, all of which may be important contributors to epileptogenesis. In the current proposal we will examine how BDNF signals through the JAK/STAT pathway to control GABAR subunit expression in the brain and its potential role in seizure- susceptibility. Specifically, we propose to: I. Determine how BDNF activates the JAK/STAT pathway. II. Determine the region and cell specificity of JAK/STAT activation in vivo after SE. III. Determine whether animals can be rescued from epilepsy development via manipulation of the BDNF-induced JAK/STAT pathway before or after SE. Results of these studies will provide new information about the dynamic interactions of BDNF and the JAK/STAT signaling cascade in its regulation of brain inhibition, especially as it pertains to the formation of a1 containing GABARs, and have the promise of facilitating the development of new therapies for the prevention, treatment or cure of epilepsy, as well as other nervous system disorders that share a change in the functional expression of a1 containing GABARs.

Public Health Relevance

Epilepsy and seizures affect over 3 million Americans of all ages, and 50,000,000 people worldwide. Over thirty percent of patients with epilepsy have seizures that cannot be controlled with current treatments and up to 50,000 people die each year from seizures and related causes. The proposed studies seek to find new ways of treating and preventing epilepsy by identifying and then reversing the changes in brain cells that lead to this condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS051710-08S1
Application #
8526721
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2005-04-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$77,297
Indirect Cost
$26,776
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Thomas, Ajay X; Cruz Del Angel, Yasmin; Gonzalez, Marco I et al. (2016) Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery. eNeuro 3:
Raible, Daniel J; Frey, Lauren C; Del Angel, Yasmin Cruz et al. (2015) JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI. Exp Neurol 271:445-56
González, Marco I; Grabenstatter, Heidi L; Cea-Del Rio, Christian A et al. (2015) Seizure-related regulation of GABAA receptors in spontaneously epileptic rats. Neurobiol Dis 77:246-56
Grabenstatter, H L; Carlsen, J; Raol, Y H et al. (2014) Acute administration of the small-molecule p75(NTR) ligand does not prevent hippocampal neuron loss or development of spontaneous seizures after pilocarpine-induced status epilepticus. J Neurosci Res 92:1307-18
Grabenstatter, H L; Del Angel, Y Cruz; Carlsen, J et al. (2014) The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol Dis 62:73-85
Scharfman, Helen E; Brooks-Kayal, Amy R (2014) Is plasticity of GABAergic mechanisms relevant to epileptogenesis? Adv Exp Med Biol 813:133-50
Grabenstatter, Heidi L; Cogswell, Meaghan; Cruz Del Angel, Yasmin et al. (2014) Effect of spontaneous seizures on GABAA receptor α4 subunit expression in an animal model of temporal lobe epilepsy. Epilepsia 55:1826-33
Gonzalez, Marco I; Cruz Del Angel, Yasmin; Brooks-Kayal, Amy (2013) Down-regulation of gephyrin and GABAA receptor subunits during epileptogenesis in the CA1 region of hippocampus. Epilepsia 54:616-24
Grabenstatter, Heidi L; Russek, Shelley J; Brooks-Kayal, Amy R (2012) Molecular pathways controlling inhibitory receptor expression. Epilepsia 53 Suppl 9:71-8
Gonzalez, Marco I; Brooks-Kayal, Amy (2011) Altered GABA(A) receptor expression during epileptogenesis. Neurosci Lett 497:218-22

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