Shih, P; (2012) Regulation of Multidirectional Communication within Tripartite Synapses in the Hippocampus. Doctoral thesis , UCL (University College London).

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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.

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