My primary research area is glial cell biology in health and disease. Three outstanding events determined my research career. First, my PhD with Joan Abbott (King’s College London) introduced me to glial cells. Then, I was first introduced to the optic nerve model in my postdoc with Bruce Ransom at Yale University, USA. Finally, in my first tenured position at Guy’s and St Thomas’, I met Martin Berry, who stimulated my interest in neurodegeneration. I was awarded a personal Chair at King’s College London in 2002 and moved to Portsmouth in 2006, where I hold a personal Chair. I am currently Director of the Institute of Biomedical and Biomolecular Sciences (IBBS), the flagship research institute at the University of Portsmouth. I have been invited to write and speak on glial cell biology on numerous occasions, and I have written 2 books on glial cell biology, with my close friend and colleague Alex Verkhratsky (Manchester).
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My group uses multiple cell biological, genetic, molecular, anatomical and physiological techniques to study glial cell biology in health and diseases such as Multiple Sclerosis, glaucoma, epilepsy, ischemia, cerebral palsy, stroke and degeneration (reviewed in Butt et al. 2004; Bolton & Butt, 2005). A major interest of my group is the regulation of glial cell fate and the mechanisms controlling myelination, and I have recently become interested in glial cells of the enteric nervous system, which benefit from collaboration with members of IBBS, together with a number of national and international groups (see below).
We are currently funded by the BBSRC which builds on a recent MRC grant to examine the mechanisms by which the Kir4.1 subtype is essential for glial functions, in order to inform on the pathophysiology of general seizure susceptibility, CNS injury, and white matter pathology. Our studies in the global Kir4.1 knock out mouse demonstrate severe astroglial depolarization, dysregulation of extracellular K+ homeostasis, and increased seizure susceptibility (Bay & Butt, 2012). In addition, we determined a novel function for TASK-1 channels in oligodendrocytes and their response to ischemia (Hawkins & Butt, 2012).We are currently funded by the BBSRC to control the temporal and cell-specific expression of Kir4.1 in glia, which will provide a major advance in our understanding of these channels in the brain. In addition, using genomic analysis we have identified a critical function for novel Kir7.1 channels in glial cells.
Neurotransmitter function in glia
We resolved the perinodal contacts formed by astrocytes and NG2-glia (OPC) at nodes of Ranvier (Butt et al., 1999). In a BBSRC funded grant we identified a multiphase axon-glial signalling mechanism in which axons release glutamate to signal onto astrocytes, which in turn release the gliotransmitter ATP to propagate calcium signals to neighbouring NG2-glia and oligodendrocytes (Hamilton et al., 2008, 2009). The functions of glial neurotransmitter signalling are unresolved (reviewed in Butt, 2006 and 2011), but in our MRC-funded project we have now identified a role for ATP signalling in regulating glial potassium channels and in our Marie Curie funded project (EduGlia) we have identified a function for metabotropic glutamate receptors in promoting the survival of oligodendrocytes in ischemia. These findings have important implications for epilepsy and stroke.
Mechanisms of Oligodendrogenesis and myelination
We are funded by the Multiple Sclerosis Society to examine the mechanisms that regulate oligodendrocyte differentiation and myelination. We have identified a profound role for GSK3b as a negative regulator of oligodenrogenesis and myelination (Azim & Butt, 2011). In addition, we have identified a novel function for FGF2 as a positive regulator of oligodendrocyte differentiation, which resolves controversy in this field (Azim et al., 2012). Currently, we are funded by the MS Society to examine the role of Gas6 signalling. In addition, in projects funded by the Anatomical Society and HEIF, we are using genomic analysis and high throughput sequencing to identify new gene targets in glia and developing new chemicals to target these signalling pathways. Our primary aim is to identify mechanisms that regulate neurogenesis.
A key reason why axon regeneration in the adult CNS fails is the glial scar, which acts as a biochemical barrier or ‘sink’ for growing axons (we reviewed this in Sandvig et al., 2004). The International Spinal Research Trust is funding a collaborative project with Dr Liz Bradbury (King’s College London), to develop a combinatorial approach of inhibiting GSK3b and using ChABC treatment to promote regrowth of axons, reformation of functional connections, and recovery of function in the CNS.