Bazargani, N; (2016) Astrocyte control of neurotransmitter signalling. Doctoral thesis , UCL (University College London).

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Abstract

Astrocytes interact with, and regulate the activity of, neurons by various mechanisms. They can release molecules known as gliotransmitters which act on neuronal receptors, or they can regulate the concentration of neurotransmitters in the extracellular space through the expression of transporters. In this thesis I describe experiments on hippocampal astrocytes and neurons that examine both of these mechanisms. By recording glutamate transporter currents in astrocytes and NMDA-evoked currents in pyramidal neurons, I demonstrate that a relatively understudied G protein coupled receptor present in astrocytes, GPCR37L1, decreases the activity of astrocyte glutamate transporters and decreases neuronal NMDA receptor activity, presumably by regulating the release of modulatory molecules from astrocytes. In ischaemia, expression of GPCR37L1 and addition of an analogue of its agonist, prosaposin, are neuroprotective. This presumably reflects the smaller NMDA receptor-evoked Ca2+ entry occurring when GPR37L1 is active, and may also reflect decreased release of glutamate by reversal of glutamate transporters. A similar approach is used to show that the modulatory neurotransmitter noradrenaline reduces glutamate uptake currents in astrocytes. This action of noradrenaline is blocked by buffering intracellular calcium concentration in astrocytes and by blocking adrenergic receptors that lower the concentration of cyclic AMP. Furthermore, I demonstrate that the intracellular protein nischarin, shown previously by the Attwell and Kittler groups to interact with astrocyte GLT-1 glutamate transporters, decreases astrocyte glutamate transport. Lastly, I provide evidence for a role of astrocyte calcium signalling in maintaining the firing frequency of inhibitory interneurons in hippocampus. I also assessed the involvement of calcium concentration rises in astrocytes in regulating excitatory neurotransmission and the effect of noradrenaline on synaptic transmission to pyramidal cells. Overall, I demonstrate signalling mechanisms that regulate glutamate uptake by astrocytes (via GPCR37L1, nischarin, and adrenergic receptors), and how astrocytes modulate excitatory neurotransmission (presumably through the release of gliotransmitters) or maintain inhibitory transmission (through Ca2+ signalling).

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