Stability of neural circuit function

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 how strongly they 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. It is, therefore, implicit that individual neurons have an inbuilt 'sense' of what is an appropriate level of activity. How such a reference-level develops and what the molecular components of the system are remains to be determined. We have identified a novel period in early neural circuit formation where manipulation of neural activity is sufficient to permanently change functional stability of mature neural circuits. We hypothesize that this period is required for the establishment of suitable activity-reference points that will form the foundation of on-going homeostatic mechanisms. 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 activity regulation are now widespread and present in animals from insects to mammals. However, although now established, our understanding of such mechanisms is poor. Key to understanding homeostasis will be the determination of how neurons transduce the level of synaptic excitation they are exposed to and how they 'sense' whether this is an appropriate amount. It is implicit in all homeostatic mechanisms that neurons/networks strive to maintain an appropriate level of activity. But how is such a level encoded with individual neurons/networks?

Our demonstration of a sensitive period during early neural circuit formation, where activity manipulation has lasting effects to neural circuit function, is consistent with this being a period during which neurons encode activity-limits which will form the basis of on-going homeostatic mechanisms. Unequivocal demonstration of this would represent a significant step-change in understanding of neural circuit development, which may also prove exploitable for the prevention of neurological disease (e.g. epilepsy).

Although demonstrated to exist, we do not yet understand how activity during this sensitive period alters aspects of neuron/network function, nor which biological pathways are involved. 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 beneficiaries of this work can be divided into 2 main groupings:

The identification and understanding of genes, and their signaling pathways, will extend beyond the immediate field of epilepsy. Understanding how neural circuits form and maintain stability of function is a key area of research. Many neurological disorders are believed to arise from inappropriate development of neural circuits. Moreover, brain degeneration during ageing contributes to the varied forms of dementia that are increasing in prevalence. Because of this, our research will also be of significance to the many neuroscientists actively seeking to understand how neural circuits develop and function throughout the human lifetime.

The development of treatments for disease requires the involvement of large pharmaceutical companies. However, nearly all treatments currently available can trace their origins 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 epilepsy. I have initiated a collaboration with UCB, one of the leading pharma companies involved in epilepsy research.


Communications & Engagement

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

Through direct contact with Charities such as Epilepsy Research UK and The International League Against Epilepsy. We will inform such charities of our work and highlight, in particular, the utility of using non-mammalian animal models (which is usually under-appreciated). We have taken this approach for our work with Drosophila.
The University of Manchester has an active out-reach program and the Manchester Fly Facility is an active member of that program. The use of flies for epilepsy research is an active-part of the program used to explain the benefits of insects for disease-research. We have incorporated Drosophila models of seizure into this program to explain how research can be translated across species.

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. I have written short articles for charity newsletters (http://www.epilepsyresearch.org.uk/a-research-update-from-the-university-of-manchester/) and often speak at meetings - e.g. NorthWest Epilepsy Group - which consists mainly of GPs and specialist nurse practitioners.

I also have a dedicated lab website which I use to advertise the type of research that we carry out (http://personalpages.manchester.ac.uk/staff/Richard.Baines/default). 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.

Collaboration

I have set-up an informal consortium with epilepsy groups at both Liverpool (Sills, Morgan) and Sheffield (Cunliffe). The aim of this collaboration is to develop a virtual pipeline to enable findings obtained in model systems (worms, flies and fish) to be promptly translated to rodent models of epilepsy. This consortium has the support of UCB - a leading pharmaceutical company researching epilepsy treatments. It also has the active support of epilepsy consultants (Liverpool and Salford).

Exploitation & Application

Drosophila offers the opportunity to develop cheap, large-scale, drug screens that are a viable alternative to using rodents. The genes that we identify to have anticonvulsant activity when knocked-down will identify potential novel targets for the development of new generation antiepileptic drugs. We will pursue these avenues through collaborations with both academic and industrial scientists.