Neurosteroid modulation of GABA-inhibition in vivo: central auditory pathway models

中枢神经系统中所有处于较高水平的神经元都会对来自其他神经元的各种兴奋性和抑制性输入（突触）的结果做出反应。大多数快速作用的抑制是由氯离子通过通道内流介导的，该通道由神经递质GABA门控。被称为GABA α-受体的该通道已知被广泛的药理学试剂（例如安定、乙醇、许多麻醉剂）调节，所述药理学试剂可以增强或抑制其功效。也有充分的理由得出结论，认为内源性物质具有调节能力。已知脑合成的类固醇（神经类固醇）对GABA α受体的功效具有有效的增强作用，并且已经涉及许多临床情况，包括月经周期相关的抑郁症。其他人的工作表明，神经类固醇的快速合成可以增加对焦虑诱导刺激的抑制作用。我们最近的工作表明，神经类固醇介导的听觉中脑区域的抑制诱导增加。这项研究的一个令人惊讶的方面是，神经类固醇似乎也介导了持续的抑制水平。现在，这使我们能够使用听觉通路中的许多抑制性相互作用作为研究神经类固醇调节GABA抑制在正常脑功能中的作用的潜在模型。这一点很重要，因为许多药物治疗都有改变神经类固醇合成的副作用。我们还将使用神经创伤的听觉系统模型来检查神经类固醇在增加抑制中的作用（以对抗潜在的致命的兴奋性增加）。这项工作将涉及电生理功能测量和使用电喷雾质谱仪直接测量亚微克脑组织样本中的神经类固醇的高灵敏度分析协议的开发。

All neurons at higher levels of the central nervous system signal in response to the outcome of various excitatory and inhibitory inputs (synapses) from other neurons. Most of the fast-acting inhibition is mediated by chloride ion influx through a channel which is gated by the neurotransmitter GABA. Termed the GABAa-receptor, this channel is known to be modulated by a wide range of pharmacological agents (e.g. valium; ethanol, many anaesthetics) which may enhance or suppress its efficacy. There are also good reasons for concluding that there is a capacity for modulation by endogenous substances. Brain synthesized steroids (neurosteroids) are known to have a potent enhancement effect upon the efficacy of GABAa-receptors, and have been implicated in a number of clinical situations, including menstrual cycle related depression. Work of others has shown that rapid synthesis of neurosteroids acts to increase inhibition in response to anxiety-inducing stimuli. Our recent work has shown that neurosteroids mediate an induced increase in inhibition in the auditory midbrain area. A surprising aspect of that study was that neurosteroids also appear to mediate ongoing levels of inhibition. This now allows us to use the many inhibitory interactions in the auditory pathway as potential models for studying the role of neurosteroid modulation of GABA inhibition in normal brain function. This is important because a number of medical treaments have the side effect of changing the synthesis of neurosteroids. We will also use an auditory system model of neurotrauma to examine the role of neurosteroids in increasing inhibition (to counter a potentially lethal increase in excitability). The work will involve electophysiological functional measurements and the development of highly sensitivity analytical protocols using an electrospray mass spectrometer for direct measurement of neurosteroids in submicrogram samples of brain tissue.