ROLE OF SOMATOSTATIN IN NORMAL AND EPILEPTIC BRAIN

本研究的目的是确定生长抑素(SST)在正常和癫痫神经传递中的作用和机制。长期以来，SST一直被认为在癫痫中发挥作用，但其功能尚不清楚。我们计划的研究基于以下几点：1)我们已经证明，SST显著降低了海马区CA1和CA3区的癫痫样活动。SST既作用于诱发的癫痫样事件，也作用于自发的癫痫样事件，表明这种多肽可能作用于限制癫痫通过海马体和其他边缘结构的传播。2)SST似乎能特异性地减少反复出现的兴奋性前馈神经传递，而兴奋性前馈神经传递对癫痫样事件的发生至关重要。癫痫组织中反复出现的兴奋性突触增多。3)海马区最一致的发现之一是齿状回门区选择性丢失含SST的神经元。这种缺失的功能后果尚不清楚，SST在齿状体内的作用也尚未确定。4)已经建立了SST多肽基因或选择性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在齿状体内具有抑制作用。因此，这项建议的具体目的是：1)研究SST对齿状体内神经传递的影响，齿状体内是癫痫事件进入海马体的大门。2)观察SST对癫痫组织突触重塑特征的影响。3)开始研究SST或SST受体基因敲除小鼠的兴奋性和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.