Endocannabinoids and tonic GABA in the dentate gyrus

描述（由申请人提供）：这是一项基础科学提案，旨在使用体外电生理和光学技术来进一步了解负责调节门门苔藓细胞突触输入活动的神经生理机制。这些不寻常的兴奋性局部回路神经元接受来自各种内在和外在来源的强谷氨酸能、gaba能和可能的胆碱能神经支配。苔藓细胞的正常功能被认为在海马的信息处理和记忆形成中起着重要作用，而它们的丧失和/或功能障碍与颞叶癫痫的病因有关。初步数据表明，苔藓细胞的抑制性和兴奋性输入的活性都是由去极化诱导的内源性大麻素释放调节的。本提案的目的1将提供由苔藓细胞激活启动的大麻素依赖信号的完整表征，并检查突触后胆碱能受体在调节内源性大麻素释放阈值中的作用。初步数据还表明，突触前GABA能受体在门门苔藓细胞的一些兴奋性传入神经中表达，进一步表明这些受体可能受到环境GABA的强直性抑制。因此，Aim 2将关注环境GABA作为这些兴奋性事件的潜在调节剂，并最终确定内源性大麻素介导的逆行信号传导与抑制性张力之间是否存在有用的关系。最后，Aim 3将验证该系统中内源性大麻素介导的逆行信号被慢性暴露于天然和/或合成大麻素激动剂而受损的假设。这些实验可能揭示在齿状回兴奋性、信息处理和记忆形成的调节中涉及的特定神经生理机制，并进一步确定它们在慢性药物滥用模型中如何随时间改变。

DESCRIPTION (provided by applicant): This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of the neurophysiological mechanisms responsible for modulating the activity of synaptic inputs to hilar mossy cells. These unusual excitatory local circuit neurons receive strong glutamatergic, GABAergic, and likely cholinergic innervation from a variety of intrinsic and extrinsic sources. Normal function of mossy cells has been postulated to play a prominent role in information processing and memory formation in the hippocampus, while their loss and/or dysfunction has been implicated in the etiology of temporal lobe epilepsy. Preliminary data indicate that the activity of both inhibitory and excitatory inputs to mossy cells is modulated by depolarization-induced release of endogenous cannabinoids. Aim 1 of this proposal will provide a complete characterization of cannabinoid dependent signaling initiated by activation of mossy cells, and examine the role of postsynaptic cholinergic receptors in modulating the threshold for endocannabinoid release. Preliminary data has also indicated that presynaptic GABAergic receptors are expressed on some excitatory afferents to hilar mossy cells and further suggested that these receptors are likely subject to tonic inhibition by ambient GABA. Thus, Aim 2 will focus on ambient GABA as a potential modulator of these excitatory afferents and will ultimately determine if there is a useful relationship between endocannabinoid mediated retrograde signaling and inhibitory tone. Finally, Aim 3 will test the hypothesis that endocannabinoid mediated retrograde signaling in this system is impaired by chronic exposure to natural and/or synthetic cannabinoid agonists. These experiments may expose specific neurophysiological mechanisms that are fundamentally involved in regulation of excitability, information processing, and memory formation in the dentate gyrus, and further determine how they are altered over time in a chronic model of drug abuse.