Abstracts

Rationale: Neonatal status epilepticus (SE) causes minimal acute brain injury, typically does not lead to epilepsy, but still may cause long-term functional deficits. An important factor in early brain development is the presence of depolarizing GABAAergic signaling, that enhances calcium-sensitive neuronal processes involved in neuronal growth and differentiation. Its switch to hyperpolarizing GABAA responses follows region and gender specific patterns. Aberrant persistence of excitatory GABAAergic signaling occurs in the adult epileptic hippocampus and has been proposed to contribute to the generation of interictal epileptic discharges. This study examines the effects of recurrent neonatal SE and separation stress upon the timing of GABAAergic switch in CA1 pyramidal neurons. Methods: Three episodes of kainic acid induced SE were induced in rats at postnatal days (PN) 4, 5 and 6 (KA456). Control rats were either naïve (CON) or saline injected and separated from the dam for similar periods (SS456). The timing of GABAAergic switch was studied using gramicidin perforated patch clamp of CA1 pyramidal neurons, stimulated at the stratum radiatum. Results: (1) At PN4-6, GABAAergic signaling was depolarizing in males but isoelectric or hyperpolarizing in females. (2) In males, GABAAergic switch was accelerated in both KA456 and SS456 groups compared to CON. (3) Following SE induction, female SS456 rats had significantly more hyperpolarized reversal potentials compared to CON. (4) Female KA456 rats only transiently regained their depolarizing GABAA receptor signaling following SE. Conclusions: The timing of GABAA receptor switch is gender-specific in CA1 pyramidal neurons. Neonatal separation accentuates the hyperpolarizing GABAA receptor responses in both sexes, irrespective of the status of the initial GABAA receptor signaling. The effects of kainic acid induced SE were different in neurons with depolarizing vs hyperpolarizing GABAA responses. Depolarizing GABAA responses after SE occurred only in neurons with hyperpolarizing GABAA responses at the time of seizure induction, but not in those with depolarizing responses. The SE-induced disruption of the normal pattern of GABAA receptor signaling in developing rats may potentially disupt normal patterns of brain development and communication and could contribute to the long term functional sequelae that may occur as a result. Grant support: NINDS NS45243, NS20253, and RSRF.