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Projects
We use electrophysiological, fluorescent imaging and biochemical techniques in cerebellar slice, culture, and cell suspension preparations. Our work falls into three broad themes:
Neuron to glial cell transmission in the cerebellum
Astrocyte processes envelop synapses throughout the brain, and express neurotransmitter receptors and transporters that detect and clear transmitter released into the extrasynaptic space during synaptic transmission. We use the Bergmann glia of the cerebellum, specialized astrocytes closely associated with the Purkinje neurons, to explore the roles of this neuron-glial communication in cerebellar function. We have discovered that the currents generated in Bergmann glia by glutamate receptor and transporter activation exhibit both short- and long-term plasticity, and that the strength of this neuron-glia transmission can vary independently of the strength of transmission at the adjacent synapse. We hope to determine the mechanism and physiological role of this glial plasticity
Nitric oxide and astrocyte Ca2+ signalling
The highly-diffusible and reactive messenger nitric oxide (NO) triggers the accumulation of the second messenger cGMP in target cells through the activation of the NO receptor, guanylyl cyclase (NOGCR). Exposure of cerebellar cell suspensions and slices to NO leads to the accumulation of cGMP in astrocytes to high micromolar concentrations. The role of cGMP signalling in astrocytes is unknown, but in many other cells the NO and Ca2+ signalling pathways interact. We are exploring the potential roles of NO in the modulation of astrocyte Ca2+ signalling.
Kinetics of Ca2+ signal transduction
Astrocytes express receptors for a wide range of physiological agonists, which are linked by the common mechanism of InsP3-dependent Ca2+ release from internal stores. Given that these agonists (e.g. histamine, glutamate, ATP) would be predicted to play different physiological roles, the question arises as to how astrocytes can discriminate between agonists that use a common second messenger, and mount a response appropriate to the physiological signal being conveyed. One possibility, which we are exploring, is that the kinetics of the Ca2+ signal generated by different agonists carries information about the identity of the agonist that initiated it. How any such variation is achieved will be investigated.
