Sexually dimorphic expression of KCC2 and GABA function

• Published in: Epilepsy research Vol. 80; no. 2; pp. 99 - 113
• Main Author: Galanopoulou, Aristea S
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.08.2008; Elsevier
• Subjects: Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Autism; Biological and medical sciences; Brain - metabolism; Epilepsy; GABA; gamma-Aminobutyric Acid - physiology; Gene Expression Regulation - physiology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus; Humans; K Cl- Cotransporters; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Pharmacology. Drug treatments; Sex; Sex Characteristics; Signal Transduction; Substantia nigra; Symporters - metabolism; GABA; Autism; Substantia nigra; Epilepsy; Hippocampus; Sex; Nervous system diseases; Central nervous system; Developmental disorder; Encephalon; Cerebral disorder; Locus niger; Central nervous system disease; Neurotransmitter
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2008.04.013

Summary GABAA receptors have an age-adapted function in the brain. During early development, they mediate depolarizing effects, which result in activation of calcium-sensitive signaling processes that are important for the differentiation of the brain. In more mature stages of development and in adults, GABAA receptors acquire their classical hyperpolarizing signaling. The switch from depolarizing to hyperpolarizing GABAA -ergic signaling is triggered through the developmental shift in the balance of chloride cotransporters that either increase (i.e. NKCC1) or decrease (i.e. KCC2) intracellular chloride. The maturation of GABAA signaling follows sex-specific patterns, which correlate with the developmental expression profiles of chloride cotransporters. This has first been demonstrated in the substantia nigra, where the switch occurs earlier in females than in males. As a result, there are sensitive periods during development when drugs or conditions that activate GABAA receptors mediate different transcriptional effects in males and females. Furthermore, neurons with depolarizing or hyperpolarizing GABAA -ergic signaling respond differently to neurotrophic factors like estrogens. Consequently, during sensitive developmental periods, GABAA receptors may act as broadcasters of sexually differentiating signals, promoting gender-appropriate brain development. This has particular implications in epilepsy, where both the pathophysiology and treatment of epileptic seizures involve GABAA receptor activation. It is important therefore to study separately the effects of these factors not only on the course of epilepsy but also design new treatments that may not necessarily disturb the gender-appropriate brain development.