Velísková Jana, Claudio Olga I, Galanopoulou Aristea S, Lado Fred A, Ravizza Teresa, Velísek Libor, Moshé Solomon L
Department of Neurology, Montofiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461, USA.
Epilepsia. 2004;45 Suppl 8:6-12. doi: 10.1111/j.0013-9580.2004.458002.x.
Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age- and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age- and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions of gamma-aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive "anticonvulsant" region is located in the SNRanterior, whereas the GABAA-sensitive "proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15-21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age.
We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age- and sex-specific features of the SNR.
Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the "female" SNR. The "proconvulsant" SNR region does not develop in the absence of testosterone in the immediate postnatal period. The "male" type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, only beta estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes.
The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimol-induced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.
发育和性激素是癫痫易感性的重要决定因素。癫痫在未成熟大脑中比在成熟大脑中更容易发生。男童患癫痫或不明原因癫痫发作的发生率高于女童。癫痫抑制神经网络发育中的性别特异性差异可能至少部分解释了这种与年龄和性别相关的癫痫易感性增加。黑质网状部（SNR）对癫痫的控制可受到年龄和性别特异性方式的影响。在成年雄性大鼠SNR中，两个在地形上离散的区域（SNR前部和SNR后部）通过对局部注入γ-氨基丁酸（GABA）A类药物（如蝇蕈醇）使用不同的输出网络，对癫痫产生不同的影响。对GABA A敏感的“抗惊厥”区域位于SNR前部，而对GABA A敏感的“促惊厥”区域位于SNR后部。在出生后第15 - 21天的未成熟雄性大鼠中，SNR在地形上没有分离，当在SNR前部或SNR后部注入GABA能药物时会产生相似的效果。仅存在一个对GABA A敏感的促惊厥网络。相比之下，雌性SNR不包含任何介导蝇蕈醇相关促惊厥作用的区域。与成年大鼠一样，未成熟雌性大鼠在任何年龄都不会形成促惊厥的SNR区域。
我们测量了向出生时阉割的雄性大鼠SNR注入蝇蕈醇对癫痫发作的影响，以更好地了解睾酮对SNR年龄和性别特异性特征形成的影响。
新生期阉割永久性改变了蝇蕈醇敏感的SNR对癫痫发作的影响的成熟过程。新生期阉割大鼠的SNR在功能上的发育类似于“雌性”SNR。在出生后早期缺乏睾酮的情况下，“促惊厥”的SNR区域不会发育。通过恢复睾酮水平可在新生期阉割大鼠中诱导出“雄性”类型的SNR效应，或通过人为提高睾酮水平在雌性大鼠中诱导出该效应。分别由睾酮还原和芳香化产生的二氢睾酮和雌激素是睾酮作用的直接介质。在出生后第0天，仅β雌激素受体在雄性和雌性的SNR中表达相同，可能是睾酮介导两性效应的原因。
以GABA A受体亚基组成、蝇蕈醇诱导的电生理反应以及输出网络的连接性为特征的SNR GABA能神经元的表型，每个都可能因睾酮的存在而改变。与雄性相比，雌性出生后第15天SNR神经元中较高的KCC2信使核糖核酸（mRNA）表达可能是蝇蕈醇诱导的电生理反应中性别相关差异的原因。总之，越来越多确凿的证据表明SNR中存在性别相关差异，这表明出生后睾酮是促惊厥或抗惊厥回路发育中的关键因素。认识到SNR中与性别和年龄相关的特征有望将这些发现转化为癫痫疾病的特异性和有效治疗方法的开发。
