Activity-dependent plasticity in an associative hippocampal circuit: mechanisms, synaptic learning rules and involvement in disease

海马齿状回(DG)在记忆形成中起着关键作用，它通过改变记忆的模式 皮层输入进入CA3区新的输出模式。尽管它的细胞和突触基础 DG中的两种兴奋细胞类型，颗粒细胞(GC)和颗粒细胞(GC) 肺门苔藓细胞(MC)起主要作用。MCS介导一种内在的、异质联想(GC-MC-GC)兴奋 环路，从相对较少的GC接收强大的输入，并提供高度分布的兴奋性 输出到大量GC。MCS将它们的联合轴突和连合轴突投射到ipsi-和 对侧DG的内分子层，在那里它们与GC的近端树突突触。此外， MCS还沿着海马区的隔颞轴投射轴突，从而在功能上连接 这个结构的不同领域。通过沿着隔颞轴投射到DG的大部分区域，MCs可以 为来自大脑皮层的信息提供重要的上下文内容。为了了解如何 信息是在DG中处理的，以及这个回路的失调如何可能导致疾病，这是一个更好的 需要具有异质缔合GC-MC-GC电路及其动态特性的知识。我们有 最近报道，MC-GC突触经历了一种新的突触前、NMDA受体非依赖性形式的 长时程增强(LTP)需要突触后脑源性神经营养因子(BDNF)/TrkB和 突触前cAMP(CAMP)/PKA信号转导。我们假设，这种新的可塑性形式增强了GC 在联合MC-GC循环回路的输出，并可能有助于依赖DG的学习和 脑部疾病，如癫痫。关于这条赛道的大量问题仍然没有得到回答。 初步数据表明，MC-GC LTP在体内是由经验和癫痫活动诱导的，是至关重要的 受内源性系统(如内源性大麻素和腺苷信号)调节，它可以 伴随着LTP的抑制性传递。在这里，使用两种实验方法的组合 在体外和体内，我们的目标是(1)表征MC可塑性的突触学习规则，(2)识别 MC-GC LTP的分子机制，(3)决定了MC-GC LTP的性质和机制 抑制性LTP，以及(4)确定体内MC可塑性的功能相关性。通过确定主要的 DG中一个关键循环回路中活动相关塑性的性质和机制，我们的建议 研究不仅可能提高我们对该回路在DG信息处理中的确切作用的理解 以及记忆编码，但也评估了这一回路的失调可能会如何导致大脑疾病， 包括癫痫、焦虑、精神分裂症和抑郁症。

The dentate gyrus (DG) of the hippocampus plays a key role in memory formation by transforming patterns of cortical inputs into new patterns of output to the CA3 area. Although the cellular and synaptic basis of this important transformation remain poorly understood, two excitatory cell types in the DG, granule cells (GC) and hilar mossy cells (MC), play a major role. MCs mediate an intrinsic, hetero-associative (GC-MC-GC) excitatory loop, receiving powerful input from a relatively small number of GCs, and providing highly distributed excitatory output to a large number of GCs. MCs project their associational and commissural axons to the ipsi- and contralateral inner molecular layer of the DG, where they synapse onto proximal dendrites of GCs. Moreover, MCs also project their axons along the septotemporal axis of the hippocampus, thereby connecting functionally diverse areas of this structure. By projecting to most areas of the DG along the septotemporal axis, MCs could provide important contextual content to the information arising from the cortex. In order to understand how information is processed in the DG and how dysregulation of this circuit may contribute to disease, a better knowledge of the hetero-associative GC-MC-GC circuit and its dynamic properties is required. We have recently reported that MC-GC synapses undergo a novel presynaptic, NMDA-receptor independent form of long-term potentiation (LTP) that requires postsynaptic brain-derived neurotrophic factor (BDNF)/TrkB and presynaptic cyclic AMP(cAMP)/PKA signaling. We hypothesize that this novel form of plasticity enhances GC output at the associative MC-GC recurrent circuit, and may contribute to DG-dependent forms of learning and brain disease, such as epilepsy. A large number of questions regarding this circuit remain unanswered. Preliminary data indicates that MC-GC LTP is induced in vivo by experience and epileptic activity, is critically regulated by endogenous systems (e.g. endocannabinoid and adenosine signaling), and it can be accompanied by LTP of inhibitory transmission. Here, using a combination of experimental approaches both in vitro and in vivo, we aim to (1) characterize the synaptic learning rules of MC plasticity, (2) identify the molecular mechanism underlying MC-GC LTP, (3) determine the properties and mechanism underlying inhibitory LTP, and (4) determine the functional relevance of MC plasticity in vivo. By identifying the main properties and mechanisms of activity-dependent plasticity in a crucial recurrent circuit in the DG, our proposed studies may not only improve our understanding of the precise role of this circuit in DG information processing and memory encoding, but also assess how dysregulation of this circuit may contribute to brain disease, including epilepsy, anxiety, schizophrenia and depression.