We are interested in understanding how embryonic neurons determine their electrical properties to ensure appropriate development of neural networks. Research in the group extends from uncovering basic mechanisms through which neurons and neural circuits develop to using the information we derive in order to develop better treatments for neurological disorders associated with inappropriate activity (primarily epilepsy).
Neurons compensate changing synaptic excitation by homeostatic modifications of electrical excitability (i.e. the ability to fire action potentials). Although well understood, the underlying molecular mechanisms remain elusive. We have identified activity-dependent regulation of sodium channel translation by the protein Pumilio is central to one such homeostatic response. Examples of this work include Mee et al., 2004, Muraro et al., 2008 and Driscoll et al., 2013.
We have also shown that increasing Pumilio is potently anticonvulsant in Drosophila. To exploit this observation we screened a chemical library and identified compounds that increase Pumilio expression. These compounds are similarly anticonvulsant and represent exciting lead compounds for new-generation antiepileptic drugs which we are now developing. See Lin et al., 2017
If neurons develop with incorrect electrical properties circuit instability can occur which may lead to epilepsy. Epilepsy is a significant disease affecting ~1% of the population and our ability to control seizure is far from adequate for many sufferers. We are using Drosophila to identify both novel targets and novel mechanisms for the design of better antiepileptic treatments. We are particularly interested in controlling splicing of voltage-gated sodium channels because we find that expression of particular splice variants reduces the likelihood and severity of seizure. Examples of this work include Marley and Baines, 2011; Lin et al., 2012; Marley et al., 2014; Lin et al., 2015 and Giachello and Baines, 2015.
Optogenetics has proven to be very powerful for the manipulation of neuronal activity in laboratory animals. However, whether this technique will be suitable for treating neurological disorders in humans remains to be
shown. An alternative approach is magnetogenetics. Unlike light, it is easy to apply a magnetic field to the human brain. We have identified Cryptochrome as a potential magnetoreceptor and are now using Drosophila genetics to determine mode-of-action. It is our hope that we will be able to control neuron activity by applying a magnetic field to brain tissue. See Marley et al., 2014 and Giachello et al., 2017.
My work uses the fruitfly, Drosophila melanogaster, for much of this work and we are very well supported by the Manchester Fly Facility.