ROLE OF SOMATOSTATIN IN NORMAL AND EPILEPTIC BRAIN

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的行动和机制。 SST长期以来一直被推测在癫痫中发挥作用，但其功能尚不清楚。 我们计划的研究是基于以下几点：1）我们已经表明，SST强烈减少海马CA1和CA3区的癫痫样活动。 SST作用于诱发和自发性癫痫样事件，这表明该肽可能起到限制癫痫发作通过海马和其他边缘系统结构传播的作用。 2)SST似乎特异性地减少复发性兴奋性前馈神经传递，这对癫痫样事件的产生至关重要。 癫痫组织中复发性兴奋性突触增加。 3)癫痫海马中最一致的发现之一是齿状回门中含有SST的神经元的选择性丢失。 这种损失的功能后果是未知的，也没有SST的作用在齿状的特点。 4)已经开发了具有SST肽基因或选择性SST受体亚型基因的无效突变（敲除）的转基因小鼠。 这些小鼠为研究内源性SST在脑中的功能提供了独特的工具。 初步研究结果提示SST在齿状回具有抑制作用。 因此，本研究的具体目标是：1）研究SST对齿状回神经传递的影响，齿状回是癫痫发作事件进入海马的通道。 2)检查SST在海马中的作用，海马经历了癫痫组织的突触重塑特征。 3)开始研究，以检查SST或SST受体敲除小鼠的过度兴奋性和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在正常和癫痫脑中的功能，并可能在癫痫和其他神经系统疾病的治疗中具有治疗意义。

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.