GABAA Receptors as Broadcasters of Sexually Differentiating Signals in the Brain

Abstract

Epileptic seizures are more common in males than in females. One of the areas that has recently been implicated in the higher susceptibility of males to seizures is the substantia nigra reticulata (SNR). Several studies support the existence of phenotypic differences between male and female infantile SNR neurons, and particularly in several aspects of the GABAergic system, including its ability to control seizures. We have recently found that at postnatal day 14-17 (PN14-17) rats, which are equivalent to infants, activation of GABA(A) receptors has different physiological effects in male and female SNR neurons. This is likely due to the differences in the expression of the neuronal-specific potassium-chloride co-transporter KCC2, which regulates the intracellular chloride concentration. In male PN14-17 SNR neurons, GABA(A)-receptor activation with muscimol causes depolarization and increments in intracellular calcium concentration and the expression of calcium regulated genes, such as KCC2. Blockade of L-type voltage-sensitive calcium channels (L-VSCC) by nifedipine decreases KCC2 mRNA expression. However, in PN14-17 females, muscimol hyperpolarizes the SNR neurons, does not increase intracellular calcium, and decreases KCC2 mRNA expression. In PN15 females, nifedipine has no effect on KCC2 mRNA expression in the SNR. This sexually dimorphic function of GABA(A) receptors also creates divergent patterns of estradiol signaling. In male PN15 rats, estradiol decreases KCC2 mRNA expression in SNR neurons. Pretreatment with the GABA(A)-receptor antagonist bicuculline or with nifedipine, prevents the appearance of estradiol-mediated downregulation of KCC2 mRNA expression. In contrast, in PN15 females, estradiol does not influence KCC2 expression. These findings show that, in infantile rats, drugs or conditions that modulate the activity of GABA(A) receptors or L-VSCCs have different effects on the differentiation of the SNR. As a result, they have the potency of causing long-term changes in the function of the SNR in the control of seizures, movement, and the susceptibility to and course of epilepsy and movement disorders.