Neurobiology of Disease Dissociated Gender-Specific Effects of Recurrent Seizures on GABA Signaling in CA1 Pyramidal Neurons: Role of GABAA Receptors

Early in development, the depolarizing GABAAergic signaling is needed for normal neuronal differentiation. It is shown here that hyperpolarizing reversal potentials of GABAAergic postsynaptic currents (EGABA ) 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 GABAAergic responses in both sexes. In males, 3KA-SE trigger a premature appearance of hyperpolarizing GABAAergic 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, EGABA 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 GABAAergic 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. GABAA receptor blockade at the time of 3KA-SE or maternal separation reversed their effects on EGABA. These data suggest that the direction of GABAA-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.