Mechanisms of plasticity at the Mossy Fiber Synapse

描述(由申请人提供)：兴奋性突触的活动驱动的修改是完善突触连接的一个极其强大的过程。海马区突触传递的长时程增强(LTP)被广泛认为是记忆形成和巩固所必需的。由于LTP分子的复杂性和异质性，许多细胞机制仍未完全确立。对这些基本过程的完整描述将使我们能够理解导致记忆存储和提取中断的神经疾病的病理。苔藓纤维突触是海马区CA3区的主要兴奋性输入之一。CA3的循环网络在联想记忆的存储和检索中特别重要。苔藓状纤维突触对该网络的调节至关重要，因此对海马区的功能起着中心作用。苔藓纤维的可塑性表现出一些非常有趣的特性。LTP在突触的突触前终末表达，但在诱导部位上仍存在争议。最近的研究表明，突触后机制在苔藓纤维LTP的诱导和跨突触信号传递到突触前的过程中发挥了作用，这种作用是由Eph受体-ephin相互作用所介导的。为了进一步探索参与这一独特途径的分子，本研究将利用相关蛋白已被基因消融或突变的突变小鼠来扰乱其信号功能。此外，我们还将探索这些分子在突触前和突触后发挥作用的确切机制。这些研究将为哺乳动物大脑中的突触传递和记忆过程提供新的见解。

DESCRIPTION (provided by applicant): Activity driven modification of excitatory synapses is an exquisitely powerful process for the refinement of synaptic connections. Long-term potentiation (LTP) of synaptic transmission in the hippocampus is widely accepted to be integral to the formation and consolidation of memories. Due to the complexity and heterogeneity of the molecules underlying LTP, many of the cellular mechanisms are still not fully established. A complete description of these fundamental processes will allow us to understand the pathology of neurological disorders that result in the disruption of memory storage and retrieval. The mossy fiber synapse provides one of the main excitatory inputs to the CA3 region of the hippocampus. The recurrent network of the CA3 is particularly important in the storage and retrieval of associative memories. The mossy fiber synapse is critical to the modulation of this network and therefore is central to hippocampal function. Mossy fiber plasticity demonstrates some very interesting properties. LTP is expressed in the presynaptic terminal of the synapse, however there is still controversy over the site of induction. Recent findings have demonstrated a role for postsynaptic mechanism in the induction of mossy fiber LTP followed by trans-synaptic signaling to the pre-synapse, mediated by Eph receptor-ephrin interactions. In order to further explore the molecules involved in this unique pathway, this study will make use of mutant mice in which the relevant proteins have been genetically ablated or mutated to disrupt their signaling function. In addition, we will explore the exact pre- and postsynaptic mechanisms by which these molecules exert their action. These studies will provide new insight relevant to synaptic transmission and memory processes in the mammalian brain.