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.
