Endocannabinoids and tonic GABA in the dentate gyrus

描述(申请人提供)：这是一项基础科学建议，旨在使用体外电生理和光学技术来加深我们对负责调节肺门苔藓细胞突触输入活动的神经生理机制的理解。这些不寻常的兴奋性局部环路神经元接受来自各种内在和外在来源的强大的谷氨酸能、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区的信息处理和记忆形成中起着重要作用，而苔藓细胞的丧失和/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受到去极化诱导的内源性大麻素释放的调节。该提案的目的1将提供由苔藓细胞激活启动的大麻素依赖信号的完整特征，并研究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能受体表达在一些兴奋性传入至肺苔藓细胞上，并进一步提示这些受体可能受到环境中GABA的紧张性抑制。因此，Aim 2将重点研究环境中的GABA作为这些兴奋性传入的潜在调节器，并最终确定内源性大麻素介导的逆行信号与抑制性音调之间是否存在有用的关系。最后，目标3将测试假设，即内源性大麻素介导的逆行信号在该系统中受到长期暴露于天然和/或合成大麻素激动剂的损害。这些实验可能揭示特定的神经生理机制，这些机制从根本上涉及齿状回兴奋性、信息处理和记忆形成的调节，并进一步确定在慢性药物滥用模型中它们是如何随着时间的推移而改变的。

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.