Cerebral hypoxia resulting in acute encephalopathy can occur in neonates as a complication of congenital heart disease, cardiopulmonary arrest, or during cardiac bypass for surgical correction of cardiac anomalies. Hypoxic encephalopathy is the most common cause of neonatal seizures, and can lead to epilepsy, cerebral palsy, and mental retardation. Therapies to prevent such long-term adverse outcomes do not yet exist, as their development requires more thorough knowledge of the pathological cellular and molecular changes in brain function that result from neonatal hypoxic encephalopathy. Using a rat model, we have obtained evidence for long-lasting pathological changes in GABA-A receptor-mediated inhibitory synaptic transmission in hippocampal CA1 pyramidal neurons following neonatal hypoxia-induced seizures. We hypothesize that these changes mediate in part the epileptogenesis associated with neonatal hypoxic encephalopathy, and may have additional adverse effects on brain function.
The aims of this project are: 1) To identify specific changes in the composition and function of GABA-A receptors expressed by hippocampal CA1 pyramidal neurons following perinatal hypoxia-induced seizures; 2) To determine if mechanisms of GABA synthesis and uptake are altered in hippocampus following perinatal hypoxia-induced seizures; and 3) To determine if the intrinsic membrane properties [and numbers] of CA1 GABAergic interneurons are altered following perinatal hypoxia-induced seizures.
These aims will be achieved through a combination of whole-cell patch-clamp recordings in hippocampal slices, and western blot and immunocytochemical analyses of brains of animals that experienced neonatal hypoxia-induced seizures and their littermate controls. The goal is to identify all mechanisms of changes in GABAergic inhibition following hypoxia-induced seizures so that new targets of age-specific therapies may be identified to treat neonatal hypoxic encephalopathy and minimize the risk of chronic neurological sequelae.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047385-04
Application #
7234701
Study Section
Special Emphasis Panel (ZRG1-DBD (01))
Program Officer
Stewart, Randall R
Project Start
2004-08-01
Project End
2008-01-06
Budget Start
2007-06-01
Budget End
2008-01-06
Support Year
4
Fiscal Year
2007
Total Cost
$158,055
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Peng, Bi-Wen; Justice, Jason A; He, Xiao-Hua et al. (2013) Decreased A-currents in hippocampal dentate granule cells after seizure-inducing hypoxia in the immature rat. Epilepsia 54:1223-31
Peng, Bi-Wen; Justice, Jason A; Zhang, Kun et al. (2011) Gabapentin promotes inhibition by enhancing hyperpolarization-activated cation currents and spontaneous firing in hippocampal CA1 interneurons. Neurosci Lett 494:19-23
Peng, Bi-Wen; Justice, Jason A; Zhang, Kun et al. (2010) Increased basal synaptic inhibition of hippocampal area CA1 pyramidal neurons by an antiepileptic drug that enhances I(H). Neuropsychopharmacology 35:464-72
Foresti, Maira L; Arisi, Gabriel M; Katki, Khurshed et al. (2009) Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus. J Neuroinflammation 6:40
Zhang, Kun; Peng, Bi-wen; Sanchez, Russell M (2006) Decreased IH in hippocampal area CA1 pyramidal neurons after perinatal seizure-inducing hypoxia. Epilepsia 47:1023-8
Sanchez, Russell M; Dai, Weimin; Levada, Rachel E et al. (2005) AMPA/kainate receptor-mediated downregulation of GABAergic synaptic transmission by calcineurin after seizures in the developing rat brain. J Neurosci 25:3442-51