ROLE OF SOMATOSTATIN IN NORMAL AND EPILEPTIC BRAIN

生长抑素在正常和癫痫大脑中的作用

• 批准号: 6041589
• 负责人: MELANIE K TALLENT
• 金额: $ 22.57万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6041589
• 关键词: dentate gyrus; disease /disorder model; epilepsy; genetically modified animals; hormone receptor; hormone regulation /control mechanism; laboratory mouse; laboratory rat; nervous system regeneration; neural transmission; somatostatin; voltage /patch clamp

The objective of this study is to determine the actions and mechanisms of the peptide somatostatin (SST) in normal and epileptic neurotransmission. SST has long been speculated to play a role in epilepsy, however its function is unknown. Our planned studies are based on the following: 1) We have shown that SST strongly reduces epileptiform activity in both CA1 and CA3 regions of hippocampus. SST acts on both evoked and spontaneous epileptiform events, suggesting that this peptide may act to limit the spread of seizures through the hippocampus and to other limbic structures. 2) SST appears to specifically reduce recurrent excitatory feedforward neurotransmission which is critical to the generation of epileptiform events. Recurrent excitatory synapses are increased in epileptic tissue. 3) One of the most consistent findings in eplieptic hippocampus is the selective loss of SST-containing neurons in the hilus of the dentate gyrus. The functional consequence of this loss is unknown, nor has the action of SST in the dentate been characterized. 4) Transgenic mice have been developed with null mutations ( knockouts ) for the SST peptide gene or for selective SST receptor subtype genes. These mice provide a unique tool for studying the function of endogenous SST in the brain. Our preliminary data suggests SST has inhibitory actions in the dentate. Therefore the specific aims of this proposal are: 1) Examine the effects of SST on neurotransmission in the dentate, which acts as a gate through which seizure events enter the hippocampus. 2) Examine the effects of SST in hippocampus which has undergone the synaptic remodeling characteristic of epileptic tissue. 3) Begin studies to examine hyperexcitabilty and SST effects in SST or SST receptor knockout mice. We will perform these studies using intracellular, extracellular, and whole-cell patch clamp techniques. These studies will help determine the function of SST in normal and epileptic brain, and could have therapeutic implications in the treatment of epilepsy and other neurological disorders.

本研究的目的是确定肽生长抑素（SST）在正常和癫痫神经传递中的作用和机制。长期以来，人们一直推测SST在癫痫中发挥作用，但其功能尚不清楚。我们计划的研究基于以下内容：1)我们已经证明，SST在海马CA1和CA3区域都能强烈降低癫痫样活动。SST对诱发的和自发的癫痫样事件都有作用，这表明这种肽可能会限制癫痫发作通过海马和其他边缘结构的扩散。2) SST似乎特异性地减少了复发性兴奋性前馈神经传递，这对癫痫样事件的发生至关重要。复发性兴奋性突触在癫痫组织中增加。3)癫痫海马最一致的发现之一是齿状回门区含sst神经元的选择性丢失。这种损失的功能后果尚不清楚，也没有表征SST在齿状体中的作用。4)已开发出具有SST肽基因或选择性SST受体亚型基因零突变（敲除）的转基因小鼠。这些小鼠为研究内源性SST在大脑中的功能提供了独特的工具。我们的初步数据表明，SST在齿状细胞中具有抑制作用。因此，本提案的具体目的是：1)检查SST对齿状体神经传递的影响，齿状体是癫痫事件进入海马体的门户。2)观察SST在经历癫痫组织突触重构特征的海马中的作用。3)开始研究SST或SST受体敲除小鼠的高兴奋性和SST效应。我们将使用细胞内、细胞外和全细胞膜片钳技术进行这些研究。这些研究将有助于确定SST在正常和癫痫大脑中的功能，并可能对癫痫和其他神经系统疾病的治疗具有治疗意义。