Dissociated gender-specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons:: Role of GABAA receptors

Early in development, the depolarizing GABA(A) ergic signaling is needed for normal neuronal differentiation. It is shown here that hyperpolarizing reversal potentials of GABA(A) ergic postsynaptic currents (E-GABA) appear earlier in female than in male rat CA1 pyramidal neurons because of increased potassium chloride cotransporter 2 (KCC2) expression and decreased bumetanide-sensitive chloride transport in females. Three episodes of neonatal kainic acid-induced status epilepticus (3KA-SE), each elicited at postnatal days 4 (P4)-P6, reverse the direction of GABA(A) ergic responses in both sexes. In males, 3KA-SE trigger a premature appearance of hyperpolarizing GABA(A) ergic signaling at P9, instead of P14. This is driven by an increase in KCC2 expression and decrease in bumetanide-sensitive chloride cotransport. In 3KA-SE females, E-GABA transiently becomes depolarizing at P8-P13 because of increase in the activity of a bumetanide-sensitive NKCC1 (sodium potassium chloride cotransporter 1)-like chloride cotransporter. However, females regain their hyperpolarizing GABA(A) ergic signaling at P14 and do not manifest spontaneous seizures in adulthood. In maternally separated stressed controls, a hyperpolarizing shift in EGABA was observed in both sexes, associated with decreased bumetanide-sensitive chloride cotransport, whereas KCC2 immunoreactivity was increased in males only. GABA(A) receptor blockade at the time of 3KA-SE or maternal separation reversed their effects on E-GABA. These data suggest that the direction of GABA(A)-receptor signaling may be a determining factor for the age and sex-specific effects of prolonged seizures in the hippocampus, because they relate to normal brain development and possibly epileptogenesis. These effects differ from the consequences of severe stress.