Role of sex hormones in the sexually dimorphic expression of KCC2 in rat substantia nigra

Galanopoulou, Aristea S.; Moshé, Solomon L.

doi:10.1016/s0014-4886(03)00387-x

Cited by 50 publications

(48 citation statements)

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“…The depolarizing GABA responses in the SNR of male rats are associated with low expression of the KCC2, while the hyperpolarizing GABA responses in females correspond to higher expression of KCC2 in the SNR (Galanopoulou et al, 2003b). The SNR expression of KCC2 can be acutely modulated by exogenous administration of testosterone or its metabolites (Galanopoulou and Moshé, 2003a) at a later age (PN13-15). Galanopoulou showed that the estrogenic derivatives of testosterone maintain KCC2 expression low, facilitating therefore the appearance of depolarizing GABA A receptor responses.…”

Section: Discussionmentioning

confidence: 99%

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Giorgi

Velı́šková

Chudomel

et al. 2007

Neurobiology of Disease

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GABAergic activation of substantia nigra pars reticulata (SNR) at postnatal day (PN) 15 has sexspecific features on seizure control in vivo and electrophysiological responses in vitro. In males, the GABA A -receptor agonist muscimol has proconvulsant effects and induces depolarizing responses. In females, muscimol has no effect on seizures and evokes hyperpolarizing responses. We determined the time period during which sex hormones must be present to produce the sex-specific muscimol effects on seizures and their influence on SNR GABA A receptor-mediated postsynaptic currents. Exposure to testosterone or its metabolites (estrogen or dihydrotestosterone) during PN0-2 in females or males castrated at PN0 was sufficient to produce proconvulsant muscimol effects but did not affect the in vitro GABA responses, which remained hyperpolarizing. The data suggest that the PN0-2 period is critical for the development of the seizure-controlling SNR system; the hormonal effect on seizure control is independent from their effect on GABA conductance. Keywords substantia nigra; sex hormones; muscimol infusions; seizure; GABA; patch clamp During development, circulating sex hormones have organizational effects leading to permanent differences between males and females in distinct brain regions (Gorski, 1984). The presence or absence of testosterone, acting via its metabolites, dihydrotestosterone and estrogen, determines the future "male" or "female" brain phenotype (McEwen, 1992). In humans, the incidence of epilepsy is higher in the youngest age groups and population studies have shown that males have a higher incidence of seizures than females (Hauser, 1997). These epidemiological data strengthen the need to understand mechanisms underlying the sexdependent differentiation of the CNS, especially in relation to structures involved in seizure Correspondence: Jana Velíšková, MD, PhD, Albert Einstein College of Medicine, Department of Neurology, K312, 1410 Pelham Parkway South, Bronx, NY 10461, USA, Phone: (718) 430-2469, Fax: (718) The substantia nigra pars reticulata (SNR), a midbrain structure populated largely by GABAergic neurons, serves as a main output of the basal ganglia. The SNR is involved in the control of seizures in an age-and sex-specific fashion (Velíšková and Moshé, 2001;Velíšková and Moshé, 2006). In immature rats [postnatal day (PN) 15], localized bilateral SNR microinfusions of muscimol, an agonist at GABA A receptors, have proconvulsant effects on flurothyl-induced clonic seizures in males but not in females (Moshé et al., 1994;Velíšková and Moshé, 2001). Additionally, in vitro gramicidin patch clamp recordings in slices from PN14-17 males and females show sex-specific responses of the SNR GABAergic neurons to bath application of muscimol (Galanopoulou et al., 2003b) and to synaptically released GABA (Kyrozis et al., 2006). In males, both have depolarizing effects on the membrane potential of the SNR GABAergic neurons, while in females the response is hyperpolarizing.The majority of sex differenc...

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Section: Discussionmentioning

confidence: 99%

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Giorgi

Velı́šková

Chudomel

et al. 2007

Neurobiology of Disease

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“…Administration of testosterone to females abolishes this sex difference (Ravizza et al 2003). Testosterone or DHT, a potent androgen receptor agonist, upregulates KCC2 mRNA in both sexes, whereas estradiol downregulates KCC2 mRNA in males, but not females (Galanopoulou and Moshe 2003; Galanopoulou 2006). This opposing effect of androgen relative to estradiol suggests a complex steroid sensitivity that is dependent on the sex of the animal.…”

Section: Hormonal Modulation Of Excitation Via Effects On Gabamentioning

confidence: 99%

“…Depolarizing GABA may promote cell development in synaptically silent, immature cells, through paracrine modulation of cell morphology (Barbin et al 1993; Demarque et al 2002). Excitability in the developing substantia nigra (SN) is similarly modulated by gonadal steroids (Galanopoulou and Moshe 2003; Galanopoulou 2006). The SN plays an established role in seizure control and movement (Giorgi et al 2007; Iadarola and Gale 1992).…”

Section: Hormonal Modulation Of Excitation Via Effects On Gabamentioning

confidence: 99%

Sexual Differentiation of the Brain and ADHD: What Is a Sex Difference in Prevalence Telling Us?

Waddell

McCarthy

2010

Current Topics in Behavioral Neurosciences

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Sexual differentiation of the brain is a function of various processes that prepare the organism for successful reproduction in adulthood. Release of gonadal steroids during both the perinatal and the pubertal stages of development organizes many sex differences, producing changes in brain excitability and morphology that endure across the lifespan. To achieve these sexual dimorphisms, gonadal steroids capitalize on a number of distinct mechanisms across brain regions. Comparison of the developing male and female brain provides insight into the mechanisms through which synaptic connections are made, and circuits are organized that mediate sexually dimorphic behaviors. The prevalence of most psychiatric and neurological disorders differ in males versus females, including disorders of attention, activity and impulse control. While there is a strong male bias in incidence of attention deficit and hyperactivity disorders, the source of that bias remains controversial. By elucidating the biological underpinnings of male versus female brain development, we gain a greater understanding of how hormones and genes do and do not contribute to the differential vulnerability in one sex versus the other.

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“…These chloride concentrations can also affect tonic inhibition (Succol et al, 2012). Steroid hormones are shown to modify the expression of KCC2 in specific brain regions in male and females (Galanopoulou and Moshe, 2003; Galanopoulou, 2006; 2008c). Moreover, AP and other protective neurosteroids could have differing effects for males and females experiencing potential excitotoxic or ischemic events; damage to specific neurons could alter function of chloride transporters and thereby the protective effects of benzodiazepines (Kelley et al, 2011).…”

Section: Molecular Mechanisms Of Sex Differences In Anticonvulsant Nementioning

confidence: 99%

Sex differences in the anticonvulsant activity of neurosteroids

Reddy

2016

J of Neuroscience Research

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Epilepsy is one of the leading causes of chronic neurological morbidity worldwide. Acquired epilepsy may result from a number of conditions such brain injury, anoxia, tumors, stroke, neurotoxicity, and prolonged seizures. Sex differences have been observed in many seizures types; however there are sex-specific seizure disorders that are much more prevalent in women. Despite some inconsistencies, there is a substantial amount of data which indicates that sensitivity to seizure stimuli differs between the sexes. Men generally exhibit greater seizure susceptibility than women, while many women with epilepsy experience a cyclical occurrence of seizures that tend to center around the menstrual period, which has been termed catamenial epilepsy. Some epilepsy syndromes show gender differences with female predominance or male predominance. Steroid hormones, endogenous neurosteroids, and sexually dimorphic neural networks appear to play a key role in sex differences in seizure susceptibility. Neurosteroids such as allopregnanolone exhibit sex differences in their anticonvulsant activity. This article provides a brief overview of the evidence for sex differences in epilepsy and how sex differences influence the use of neurosteroids in epilepsy and epileptogenesis.

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Role of sex hormones in the sexually dimorphic expression of KCC2 in rat substantia nigra

Cited by 50 publications

References 48 publications

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Sexual Differentiation of the Brain and ADHD: What Is a Sex Difference in Prevalence Telling Us?

Sex differences in the anticonvulsant activity of neurosteroids

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