CELLULAR & BIOCHEMICAL MECHANISMS UNDERLYING MOSSY FIBER LONG TERM POTENTIATION

突触强度的长期、活动依赖性变化 传递在神经回路的发展中起着至关重要的作用 以及在信息存储方面。这样的变化似乎也起到了 在大脑从各种病理状态中恢复的重要作用 侮辱。最引人注目和最广泛研究的模型 观察到的变化是长时程增强(LTP) 海马CA1区锥体细胞。然而，很明显，有许多 突触可塑性的形式，以及它们的潜在机制不同。 这个项目的主要目标是阐明分子机制。 在苔藓之间的突触观察到的新形式的LTP 纤维和海马CA3区锥体细胞(MFLTP)。与加州的LTP不同 细胞，MFLTP不需要激活NMDA受体，但似乎 由突触前激活cAMP依赖的蛋白激酶诱导 (PKA)导致神经递质释放的长期增加。一个 将使用许多不同的生理和生化方法 检查MFLTP。因为MFLTP可以在单细胞培养中产生 对于齿状颗粒细胞，将有可能直接监测变化 在突触小泡的胞吐和胞吞中使用荧光染料 FML-43。将使用生化分析来监测 CAMP水平和PKA活性在多发性硬化性唇炎中的变化 确定特定的突触前磷酸蛋白，特别是 RabPhilin 3A可能参与了这种可塑性。互补性 一系列实验将在一系列突变小鼠中检测MF LTP 缺乏特定的突触前蛋白Rab3A。因为神经营养因子 似乎在经验依赖的大脑皮层中起着重要作用 可塑性，也会导致神经递质的长期增加 释放后，他们的突触活动将被检查并与MF LTP进行比较。 中枢性唇裂及其突触活动的检测与比较 神经营养因子将显著提高我们对基本的 哺乳动物大脑中突触可塑性的机制。这又反过来 将促进干预措施的发展，这些干预措施将防止 或促进从伴随着一些病理性侮辱的 神经疾病，如中风和癫痫。

Long-lasting, activity-dependent changes in the strength of synaptic transmission play a critical role in the development of neural circuits and in the storage of information. Such changes also appear to play an important role in the recovery of the brain from a variety of pathological insults. The most compelling and extensively studied model for such changes has been that form of long-term potentiation (LTP) observed in hippocampal CAl pyramidal cells. It is clear, however, that there are many forms of synaptic plasticity and that their underlying mechanisms differ. The primary goal of this project is to elucidate the molecular mechanisms underlying the novel form of LTP observed at the synapses between mossy fibers and hippocampal CA3 pyramidal cells (MF LTP). Unlike the LTP in CAl cells, MF LTP does not require activation of NMDA receptors but appears to be induced by presynaptic activation of the cAMP-dependent protein kinase (PKA) resulting in a long-lasting increase in neurotransmitter release. A number of different physiological and biochemical approaches will be used to examine MF LTP. Because MF LTP can be generated in single cell cultures of dentate granule cells, it will be possible to directly monitor changes in synaptic vesicle exocytosis and endocytosis using the fluorescent dye FMl-43. Biochemical assays will be used to monitor the time course of changes in cAMP levels and PKA activity during MF LIP as well as to determine whether specific presynaptic phosphoproteins, in particular rabphilin 3A, may be involved in this form of plasticity. A complementary set of experiments will examine MF LTP in a line of mutant mice which is lacking the specific presynaptic protein, rab3A. Because neurotrophins appear to play an important role in experience-dependent cortical plasticity and also cause long-lasting increases in neurotransmitter release, their synaptic actions will be examined and compared to MF LTP. An examination and comparison of MF LIP and the synaptic actions of neurotrophins will markedly enhance our understanding of the basic mechanisms of synaptic plasticity in the mammalian brain. This in turn will facilitate the development of interventions that will either prevent or promote recovery from the pathological insults accompanying a number of neurologic disorders such as stroke and epilepsy.