Inhibitory regulation of hippocampal CA3 neuron activity, learning, and memory

项目总结/摘要 抑制性GABA能神经元仅占大脑所有神经元的约15%，但它们的活性 对大脑功能的各个方面都至关重要，GABA神经元功能障碍涉及许多 神经系统疾病和精神疾病。特别是，抑制可能发挥着独特的， 在海马CA 3区的重要作用。在CA 3区，DG神经元与CA 3突触连接 锥体神经元通过巨大的兴奋性苔藓纤维终末和CA 3神经元使许多 经常性的联系因此，CA 3中失控励磁的可能性很高。前馈 从DG到CA 3抑制被认为是关键的，允许产生特定的兴奋性输入 有意义的活动模式。尽管抑制海马CA 3区可能很重要， 一些研究直接研究了GABA神经元活动如何控制CA 3锥体神经元 活动我们鉴定了一组树突靶向GABA神经元， 突触发生蛋白Kirrel 3。Kirrel 3蛋白是形成MF丝状伪足突触所必需的，是一种特殊的 一种兴奋性突触，连接DG神经元和GABA神经元，并介导饲料- 对CA 3的正向抑制。因为Kirrel 3必须在突触前和突触后表达， 神经元形成突触，这强烈表明Kirrel 3表达的GABA神经元是直接的 MF丝状伪足的靶点和K3-GABA神经元的研究将有助于阐明MF丝状伪足的确切功能 MF丝状伪足介导的CA 3抑制。我们将在三个目标中测试这一点， 分析到大规模功能细胞成像到行为。在整个过程中，我们将研究 通过比较这组树突靶向GABA神经元与索马的功能， 靶向不表达Kirrel 3的神经元。无论结果如何，我们的结果是预期的 促进我们对学习和记忆中GABA神经元活动的理解，并可以提供一个 研究共享突触连接基因的GABA神经元的新框架。

PROJECT SUMMARY/ABSTRACT Inhibitory GABAergic neurons comprise only about 15% of all neurons in the brain yet their activity is critical for all aspects of brain function and GABA neuron dysfunction is implicated in many neurological disorders and mental illnesses. In particular, inhibition likely plays a unique and important role in hippocampal area CA3. In the CA3 region, DG neurons synapse onto CA3 pyramidal neurons via giant excitatory mossy fiber terminals and CA3 neurons make many recurrent connections. Thus, the potential for runaway excitation in CA3 is high. Feed-forward inhibition from DG to CA3 is thought to be critical allow specific excitatory inputs to generate meaningful activity patterns. Despite the likely importance of inhibition in hippocampal area CA3, few studies have directly examined how GABA neuron activity controls CA3 pyramidal neuron activity. We identified a group of dendrite-targeting GABA neurons that commonly express the synaptogenic protein Kirrel3. Kirrel3 protein is necessary to form MF filopodia synapses, a special type of excitatory synapse that connects DG neurons to GABA neurons and mediates feed- forward inhibition to CA3. Because Kirrel3 must be expressed in both the pre- and post-synaptic neuron to make a synapse, it strongly suggests Kirrel3-expressingn GABA neurons are direct targets of MF filopodia and the study of K3-GABA neurons will shed light on the precise function of MF filopodia-mediated inhibition in CA3. We will test this in three aims spanning ultrastructural analysis to large-scale functional cell imaging to behavior. Throughout, we will examine the selectivity of this group of dendrite-targeting GABA neurons by comparing their function to soma- targeting neurons that do not express Kirrel3. Regardless of outcome, our results are expected advance our understanding of GABA neuron activity in learning and memory and could provide a new framework for studying GABA neurons that share synaptic connectivity genes.