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Sex-Dependent Signaling Pathways Underlying Seizure Susceptibility and the Role of Chloride Cotransporters

1
Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 448; https://doi.org/10.3390/cells8050448
Received: 29 March 2019 / Revised: 4 May 2019 / Accepted: 9 May 2019 / Published: 13 May 2019
(This article belongs to the Special Issue Sex Differences in Health and Diseases)
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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. View Full-Text
Keywords: seizures; epilepsy; refractory; chloride; neurotrophins; neurosteroids; neonatal; developmental disorders. seizures; epilepsy; refractory; chloride; neurotrophins; neurosteroids; neonatal; developmental disorders.
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kipnis, P.A.; Sullivan, B.J.; Kadam, S.D. Sex-Dependent Signaling Pathways Underlying Seizure Susceptibility and the Role of Chloride Cotransporters. Cells 2019, 8, 448.

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