Synaptic Transmission & Plasticity at Hippocampal Mossy Fiber Synapses: New Mechanisms and Functional Implications
Hunt, David Lewis
MetadataShow full item record
Excitatory synaptic transmission in the hippocampus is mediated by three classes of ionotropic glutamate receptors: AMPA receptors (AMPARs), NMDA receptors (NMDARs), and kainate receptors (KARs). The main goals of this thesis are to elaborate on the mechanisms of transmission and plasticity at the main excitatory synaptic input to the hippocampus proper, the mossy fiber to CA3 pyramidal neuron (MF-CA3) synapse.;Unlike AMPARs and NMDARs, which are found ubiquitously throughout the brain, KARs shows a distinct expression pattern. Native KARs at synapses mediate a characteristically slow excitatory postsynaptic current (KAR-EPSC), which was originally identified at the MF-CA3 synapse in the hippocampus. We identified Neto1 as an auxiliary subunit of native KARs. We found that the unique distribution of high-affinity KARs is determined by Neto1 because Neto1 confers KARs with high affinity agonist-binding properties. Neto1-knockout mice, exhibited a selective reduction in the amplitude and decay kinetics of MF-CA3 KAR-EPSCs. Our results indicate that two unique properties of native KARs, namely their high affinity binding pattern in the brain, and the distinctly slow kinetics of KAR-EPSCs, are endowed by the KAR auxiliary subunit Neto1. Furthermore, I demonstrate that Neto1 greatly affects the charge transferred via KARs. In Neto1-knockout mice this effect leads to decreased spike transmission and temporal fidelity of action potentials.;To analyze the influence of NMDAR plasticity at the MF-CA3 synapse on the output of CA3 cells under in-vivo like conditions, the paradigm of spike timing-dependent plasticity was adapted to the spatially selective burst-firing patterns of CA3 place cells observed in-vivo. My results demonstrate that the temporal relationship between pre and postsynaptic bursting-activity can bidirectionally regulate NMDAR-mediated transmission in a long-term manner. Bidirectional NMDAR plasticity requires differential calcium sources and group-I metabotropic glutamate receptor activation for induction. Furthermore, LTP or LTD of NMDAR-mediated transmission is expressed by exocytosis and endocytosis of NMDARs respectively. Bidirectional NMDAR plasticity imparts bidirectional modulation of MF-driven output and spike temporal fidelity in CA3 pyramidal neurons. I further reveal MF-NMDAR dependent regulation of AMPAR-mediated plasticity at anatomically more distal recurrent synapses, known to be required for linking cells together into an ensemble during memory formation. Collectively these functions of MF-NMDARs can contribute to the formation, storage, and recall of cell assembly patterns in CA3.;Following from this work are descriptions of several ancillary findings and observations that were made during the course of this research tract. In particular I will describe a hypothesis of the mechanistic basis of secondary currents elicited by NMDARs. More specifically, I will provide preliminary evidence at the MF-CA3 synapse of calcium dependent pannexin-1 hemichannel activation downstream of NMDARs that leads to large amplitude depolarizing currents and burst-firing output of hippocampal CA3 pyramidal neurons. Moreover, I suggest that pannexin-1 could serve as a key "detonator" of the MF-CA3 synapse. Owing to the detonator properties of the MF-CA3 synapse, the CA3 region is a common locus for epileptiform activity, also due in part to its high degree of recurrent connectivity. During brief bouts of activity that lead to post-tetanic potentiation, the CA3 network is particularly susceptible to over-excitation due to short-term depression of feed-forward inhibitory transmission. I present evidence that the MF-CA3 synapse may possess a built-in mechanism for dampening post-tetanic potentiation, thereby helping to maintain an appropriate level of excitation. This form of negative feedback likely involves a calcium dependent signal generated postsynaptically that exerts its effect presynaptically. Thus this may be a mechanism of synaptic homeostasis, buffering the amount of excitatory drive based on calcium readout of postsynaptic excitation. Additionally, I will expound on an observation suggesting that CA3 pyramidal neurons possess the capacity for intrinsic bistability. Bistability of neurons has been proposed as a mechanism that can support working memory. I will outline the potential relevance of this observation as well as suggest some possible experiments that may shed light on the mechanistic basis of this intriguing phenomenology. (Abstract shortened by UMI.).
- Theses and Dissertations