Abstract
Seizure incidence, severity, and antiseizure medication (ASM) efficacy varies between males and females. Differences in sex-dependent signaling pathways that determine network excitability may be responsible. The identification and validation of sex-dependent molecular mechanisms that influence seizure susceptibility is an emerging focus of neuroscience research. The electroneutral cation-chloride cotransporters (CCCs) of the SLC12A gene family utilize Na+-K+-ATPase generated electrochemical gradients to transport chloride into or out of neurons. CCCs regulate neuronal chloride gradients, cell volume, and have a strong influence over the electrical response to the inhibitory neurotransmitter GABA. Acquired or genetic causes of CCCs dysfunction have been linked to seizures during early postnatal development, epileptogenesis, and refractoriness to ASMs. A growing number of studies suggest that the developmental expression of CCCs, such as KCC2, is sex-dependent. This review will summarize the reports of sexual dimorphism in epileptology while focusing on the role of chloride cotransporters and their associated modulators that can influence seizure susceptibility.
Highlights
During development, the polarity of GABAergic neurotransmission undergoes a switch from depolarizing to hyperpolarizing [1,2]
Human studies have demonstrated that neonates that experience seizures have an increased risk for developing epilepsy later in life, such as temporal lobe epilepsy (TLE), the most common form of adult epilepsy with chronic recurrent spontaneous seizures originating from the temporal lobe
Estradiol administration to newborn rat pups increased the expression level of SPAK and OSR1 while enhancing the phosphorylation of NKCC1 [55]. These findings suggest that the WNK1-SPAK pathway, and the phoshoregulation of NKCC1 and KCC2, could be efficacious pharmacological targets to promote inhibition in epilepsy
Summary
The polarity of GABAergic neurotransmission undergoes a switch from depolarizing to hyperpolarizing [1,2]. Human studies have demonstrated that neonates that experience seizures have an increased risk for developing epilepsy later in life, such as temporal lobe epilepsy (TLE), the most common form of adult epilepsy with chronic recurrent spontaneous seizures originating from the temporal lobe. In the neonatal and immature brain, KCC2 expression is insufficient to develop this Cl- gradient, and GABAA R is found to be depolarizing [16] This results in the neonatal seizure associated pharmacoresistance to ASMs such as phenobarbital [22]. The developmental expression of KCC2 and NKCC1 is sexually dimorphic [27]; this suggests that sexually dimorphic modulation of chloride regulation may be one of the key mechanisms underlying differences in seizure susceptibility and refractoriness between sexes. The hope is that the care and management of those patients would benefit from an improved understanding of underlying sexually dimorphic mechanisms
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