Homeostatic control of neuron excitability

The nervous system must adapt and change to allow us to learn new tasks or to cope with injury and disease. One significant area of change is the amount of excitation neurons are exposed to. All neurons become 'wired' together in circuits that control our behaviours and potential to learn. These connections, termed synapses, are highly dynamic and can rapidly change their ability to either inhibit or activate partner neurons. These changes, when summed, have the potential to either leave a target neuron devoid of excitation or, by contrast, saturated. Either extreme can push neural circuits towards destabilisation and may result in diseases such as epilepsy. To guard against such extremes, neurons have developed homeostatic mechanisms to allow them to adjust how they respond to synaptic excitation. If excitation becomes too low, neurons boost their output by firing more than normal numbers of action potentials. If excitation becomes too great, these same neurons respond by reducing their action potential firing. Although well established, our understanding of the underlying components of homeostatic mechanisms is poor. Our studies utilise the fruitfly because its genome is fully sequenced and because it provides a simple model for the human nervous system.

Neurons are able to regulate membrane excitability in order to match output (i.e. action potential firing) to input (i.e. synaptic excitation). Such homeostatic mechanisms maintain membrane excitability within physiologically-acceptable limits. Observations showing such regulation are now widespread and present in animals from insects to mammals. However, although now established, our understanding of such mechanisms is poor. My laboratory has exploited the fruitfly, Drosophila melanogaster, to identify the components of one such homeostatic mechanism, which is significant in that it represents a novel mode of action: translational repression of voltage-gated sodium channel mRNA. We have identified, in both Drosophila and rat neurons, that synaptic activity regulates the expression level of a translational repressor termed Pumilio and have shown that it, and two cofactors, is required to repress translation of mRNAs that contain a specific, and identified, binding motif. These mRNAs include voltage gated sodium channels.

However, because we do not yet know important aspects of this mechanism, we are not able to fully understand its operational characteristics. Unknowns include how synaptic excitation, received at the neuronal membrane, is transduced to altered levels of Pumilio expression. This is without doubt a key step in all homeostatic mechanisms and as such, the information that we gain from this study will have significant impact to better understanding many, if not all, of the activity-dependent processes in the CNS.

The work contained within this grant is basic in nature but has clear strategic relevance in relation to the treatment and possible cure for various neurological disorders that involve altered neuronal activity (e.g. epilepsy). This work will also validate the use of an invertebrate model organism - Drosophila melanogaster - for the continued investigation of homeostatic mechanisms that are conserved in mammals. Thus it has the potential to reduce the usage of mammalian animals that are currently used for such research. As such this programme of work falls under the NC3R's initiative.

The beneficiaries of this work can be divided into 2 main groupings:

1. Our published work shows that translational repression underpins a common homeostatic mechanism in both Drosophila and rat. As such, the advantages of the fly can be exploited to provide a detailed understanding of this mechanism. Many researchers focus on activity homeostasis in the mammalian CNS and thus our work will be of considerable significance to these individuals.
2. The development of treatments for disease requires the involvement of large pharmaceutical companies. However, nearly all treatments currently available can have their origins traced back to basic research undertaken in Universities. We are very conscious of the roles that pharmaceutical companies play in development of treatments and our research will be of direct benefit to those companies actively pursuing treatments for neurological disease.


Communications & Engagement

In addition to traditional means (research publications and conferences) we will disseminate our research as follows:

1. Through direct contact with Charities such as Epilepsy Research UK (for which I contributed a news item in the March 2013 on-line newsletter). We will inform such charities of our work and to highlight, in particular, the utility of using non-mammalian animal models (which is usually under-appreciated).
2. Through contact with the Media. For example, I took part in radio 4's Material World in Nov 2008 to highlight the use of Drosophila for research in to human diseases.
3. I also have a dedicated lab website which I use to advertise the type of research that we carry out.
4. As an active member of the teaching staff at Manchester, I also use and advertise my research to undergraduates through lectures and final year projects in the hope of encouraging some to consider this area of research for their future careers. For example, past education-project students have designed and presented workshops to 6th form students on the utility of non-mammalian models for neurological research.

Collaboration

I recently obtained funding, from The Wellcome Trust, to develop a core-Drosophila facility at Manchester to encourage a greater degree of interactivity and collaboration between existing fly groups and those wishing to exploit this model system for the first time. Many researchers using mammalian models could benefit by incorporating this fly into their research programmes and this facility reduces the inertia to do so.


Exploitation & Application

Drosophila offers the opportunity to develop cheap, large-scale, drug screens that are a viable alternative to using rodents. Such screens have already been undertaken for a number of diseases, including epilepsy (by Cambria Biosciences, USA, with whom I have an active collaboration).