Tomas Bellamy
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• Career History
• Recent, selected Publications
Career History
1994-1997: BSc, Biochemistry, University of Bristol
1997-2001: PhD, Neurosciences, University College London
2001-2004: Postdoctoral Research Associate, MRC National Institute for Medical Research, Mill Hill, London
2004-present: BBSRC David Phillips Fellow, Babraham Institute
Neurone to astrocyte signalling in the cerebellum.
Brain cells can be divided into two main types: neurones, which can conduct electrical signals, and glial cells, which cannot. Consequently, glial cells have long been thought to simply support neurones, by synthesizing essential nutrients and maintaining a microenvironment favourable for electrical and synaptic transmission.
In recent years, however, it has been discovered that a class of glial cells known as astrocytes can respond to neuronal activity with biochemical signals, such as elevation of cellular calcium (Ca
2+) concentration. The roles of Ca
2+ in cell function are hugely diverse, ranging from the release of transmitters and hormones on a subsecond time scale, to the regulation of gene expression and development over months or years. Disruption of Ca
2+ signalling pathways can lead to onset of disease and death.
In the cerebellum, a brain region involved in motor coordination and learning, astrocytes respond to the release of chemical messengers during synaptic transmission, such as glutamate and nitric oxide (NO), by accumulating the second messengers Ca
2+ and cyclic GMP (cGMP).
My interest is in understanding the consequences of these signals for normal and abnormal cerebellar function. The emphasis is on how the kinetics of glutamate and NO receptors shapes cellular Ca
2+ and cGMP signals, and how differences in timing can allow discrimination between downstream targets. Modification of receptor kinetics introduces complexity and versatility into signal transduction pathways.
We have measured the rates of cGMP accumulation and degradation in cerebellar astrocytes, following exposure to NO (Figure 1, above). We found that the NO receptor responds dynamically to fluctuations in NO concentration in the nanomolar range, and desensitizes within seconds when exposed to constant concentrations. This behaviour can account for the diversity of cGMP signals observed in different cells.
More recently, we have used electrophysiology to measure currents generated in astrocytes in response to stimulation of granule neurone-Purkinje neurone synapses. The amplitude of currents generated by Ca
2+ permeable glutamate receptors in the astrocytes varied substantially with the frequency at which granule neurone parallel fibres were stimulated.
This variation, or “plasticity”, of glutamate currents ranged from short-term facilitation during high frequency stimulation, which lasted for less than a second, to long-term depression during low frequency stimulation that could last for at least half an hour (Figure 2).
Interestingly, the plasticity of glutamate currents in astrocytes differs greatly from the plasticity of currents in adjacent Purkinje neurones, suggesting that these cells operate independently in their responses to synaptic activity. The frequency of parallel fibre activity will therefore determine the size and timing of Ca
2+ influx into astrocytes.
In the future, our goal is to elucidate the spatiotemporal properties of astrocyte Ca
2+ signals generated by neuronal activity, the molecular pathways underlying the observed responses, and the consequences of astrocyte Ca
2+ signalling for cerebellar function. In this way, we hope to gain insight into the roles of astrocyte signalling in brain physiology and pathology.
Recent, selected publications
Bellamy TC (2007) Presynaptic modulation of parallel fibre signalling to Bergmann glia.
Neuropharmacology 52 368-375
http://dx.doi.org/10.1016/j.neuropharm.2006.08.009
Bellamy TC (2006) Interactions between Purkinje neurones and Bergmann glia.
Cerebellum 5 116-126
http:/dx.doi.org/10.1080/14734220600724569
Bellamy TC, Ogden D (2006) Long-term depression of neuron to glial signalling in rat cerebellar cortex.
European Journal of Neuroscience 23 581-586
http://dx.doi.org/10.1111/j.1460-9568.2005.045888.x
In recent years, however, it has been discovered that a class of glial cells known as astrocytes can respond to neuronal activity with biochemical signals, such as elevation of cellular calcium (Ca2+) concentration. The roles of Ca2+ in cell function are hugely diverse, ranging from the release of transmitters and hormones on a subsecond time scale, to the regulation of gene expression and development over months or years. Disruption of Ca2+ signalling pathways can lead to onset of disease and death.
More recently, we have used electrophysiology to measure currents generated in astrocytes in response to stimulation of granule neurone-Purkinje neurone synapses. The amplitude of currents generated by Ca2+ permeable glutamate receptors in the astrocytes varied substantially with the frequency at which granule neurone parallel fibres were stimulated.
