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Regulation of Multidirectional Communication Within Tripartite Synapses in the Hippocampus

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Regulation of Multidirectional Communication Within Tripartite Synapses in the Hippocampus Regulation of Multidirectional Communication within Tripartite Synapses in the Hippocampus Pei-Yu Shih Thesis submitted to University College London for the degree of Doctor of Philosophy January 2012 Institute of Neurology University College London 1 Declaration I, Pei-Yu Shih, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. The simulation results presented in Fig. 18 were developed by Dr. L. Savtchenko in UCL, institute of Neurology. All other experiments were conducted by me. 2 Abstract Tripartite synapses, a new concept in synaptic physiology, comprise active bidirectional communications between astrocytes, pre- and postsynaptic neurons. Although the postsynaptic neuron is often referred to as a listener due to lack of neurotransmitter release apparatus, recent studies of retrograde signals hint at its ability to transmit information back to the presynaptic neuron and astrocyte. In this thesis, I aim to provide an entry point for further exploration of this feedback regulation, focusing on the involvement of potassium ions. To this end, I used astrocytic recordings to monitor extracellular potassium changes in hippocampal slices. I found that 62.3 ± 8.0 % of astrocytic K+ current can be blocked by AP5 (an NMDA receptor antagonist). Puff application of 1 mM NMDA also induced the AP5-sensitive K+ current. Because astrocytes do not express functional NMDA receptors (Karavanova et al., 2007), this K+ current should have a neuronal origin. In mice lacking NMDA receptors selectively in CA1 pyramidal neurons, stimulation of Schaffer collaterals led to impaired AP5-sensitive K+ currents in CA1 astrocytes, pointing to the role of ‘postsynaptic’ NMDA receptors. Postsynaptic NMDA receptor activation can trigger either Ca2+-sensitive K+ channels or voltage-gated K+ channels in these neurons. However, NMDA-puff induced K+ currents in astrocytes was relatively insesnsitive to removal of extracellular Ca2+ or regional voltage change, implying the possibility of direct K+ efflux through NMDA receptors. Intriguingly, this K+ released from postsynaptic neurons was localized to active synapses and displayed activity-dependency. Releasing Mg2+ blockade of NMDA receptors by either repeated stimuli or pairing of pre- and postsynaptic activation produced supralinear increases in astrocytic K+ currents. Such a retrograde K+ signal is coupled to modulation of presynaptic Ca2+ signaling and paired-pulse ratio when sufficient fibers were stimulated. Glutamate uncaging results also revealed its potential role in modulating astrocytic glutamate transporters. My results clearly demonstrate a contribution of postsynaptic neurons via + K in shaping tripartite synaptic communication. 3 Contents Chapter 1: Introduction............................................................................................................................... 13 1. Communication within Tripartite Synapses ..................................................................... 14 + 2. Communication via K in the Tripartite Synapse ............................................................ 17 + 2.1 Range of [K ]o Variation in Physiological and Pathological Conditions ................. 18 + 2.2 K Effects on Neurons .............................................................................................. 18 + 2.2.1 Modulation of Synaptic Transmission by K ........................................................... 18 + 2.2.2 Modulation of Long-Term Plasticity by K .............................................................. 19 2.2.3 Neuronal Oscillation & Seizure ............................................................................... 19 + 2.3 K Effect on Astrocytes ............................................................................................ 21 + 2.3.1 Modulation of Glutamate Transporter by K ........................................................... 21 + 2.3.2 Modulation of Gap Junction Coupling by K .......................................................... 21 + 2.3.3 Modulation of Glycolysis by K .............................................................................. 22 + 2.4 High Contribution of Postsynaptic Neuron to [K ]o ................................................. 22 2.4.1 Axonal and Dendritic Potassium Channels .............................................................. 22 + 2.4.2 Relative Contribution of Pre- and Postsynaptic Neurons to [K ]o ........................... 24 + 3. K Signals Triggered by Glutamate Receptors on Postsynaptic Neurons ........................ 24 + 3.1 K Signals Induced by AMPA Receptors ................................................................. 25 + 3.2 K Signals Induced by NMDA Receptors ................................................................ 26 3.2.1 KCa Activated by NMDA Receptors ......................................................................... 27 3.2.2 Kv Activated by NMDA Receptors .......................................................................... 28 4. Properties of NMDA Receptors ....................................................................................... 29 4.1 Subunit Composition of NMDA Receptors ............................................................. 29 4.2 Location: Synaptic & Extrasynaptic ........................................................................ 30 4.3 Activation of NMDA Receptors by Removing Mg2+ ............................................... 31 4.4 Activation of NMDA Receptors by EPSP-bAP Pairing ........................................... 33 5. Astrocytes as Potassium Detectors .................................................................................. 35 5.1 Astrocyte Identification ............................................................................................ 35 5.1.1 Passive Astrocytes .................................................................................................... 36 5.1.2 Complex Astrocytes ................................................................................................. 36 5.1.3 Developmental Change of the Ratio Between Passive and Complex Astroctyes .... 37 5.1.4 Identification of Passive Astrocyte by SR101 .......................................................... 38 4 5.2 Astrocyte Response to Neuron ................................................................................. 39 5.2.1 Astrocytes are Intimately Associated with Synapses ............................................... 39 5.2.2 Each Astrocyte Occupies its Own Domain .............................................................. 40 5.3 Astrocytic Currents Reflect Neuronal Activity ........................................................ 41 5.3.1 Estimate of Glutamate Release by Transporter Current (TC) .................................. 42 5.3.1.1 Astrocytic Glutamate Transporters ......................................................... 42 5.3.1.2 Detecting Glutamate Time Course by Astrocyte Recording ................... 43 5.3.2 Estimation of Extracellular Potassium from IK ....................................................... 44 + 5.3.2.1 Astrocytic K Uptake Mechanisms ......................................................... 44 + 5.3.3 Detecting [K ]o Change via Astrocyte Recording .................................................... 46 6. Aims of This Study .......................................................................................................... 47 Chapter 2: Material & Methods .................................................................................................................. 48 1. Chemicals & Equipment .................................................................................................. 49 2. Model System: Hippocampal Slice .................................................................................. 53 2.1. Trisynaptic Circuit of Hippocampus ........................................................................ 53 2.2. Preparation of Hippocampal Slices .......................................................................... 55 3. Electrophysiology and Imaging Techniques .................................................................... 57 3.1. Extracellular Field Recordings ................................................................................. 57 3.1.1. Principle ................................................................................................................... 57 3.1.2. Field Potential Recording in Acute Hippocampal Slices ......................................... 58 3.1.3. Release Probability Monitored by Paired-Pulse Ratio (PPR) .................................. 59 3.2. Patch-Clamp Recording ........................................................................................... 60 3.2.1. Principle ................................................................................................................... 60 3.2.2. Patch-Clamp Recording of Astrocytes ..................................................................... 60 3.3. Puff Application ....................................................................................................... 61 3.4. Immunohistochemistry ............................................................................................. 62 3.5. Ca2+ Imaging of Presynaptic Terminals.................................................................... 62 3.5.1. Ca2+ Imaging Principle ............................................................................................
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