Molecular Epilepsy

Research Overview

The epilepsies are a common group of chronic neurological conditions that are characterised by recurrent spontaneous unprovoked epileptic seizures. Epilepsy is the second most common serious neurological disorder in the community, with approximately 9% of the population having a seizure at some stage in their lifetime and 3% developing epilepsy. A large proportion of epilepsy syndromes involve genetic alterations however the progress to date in identifying the genetic basis of epilepsy has been limited primarily to the discovery of single gene mutations that cause epilepsy in relatively rare families. For the more common types of epilepsy, it is thought that a combination of mutations in multiple genes likely determine an individual’s susceptibility to seizures, as well as the responsiveness to antiepileptic medications. 

The overriding aim of the Molecular Epilepsy Group is to identify potential molecular targets that could be the basis of much more specific and effective treatments for patients who have epilepsy, and the prevention of epilepsy in those at risk.

Another area of focus for my group is centred on investigating cardiac function in animal models of epilepsy. Cardiac electrophysiological dysfunction is common in people with epilepsy; particularly in those with a longer duration of epilepsy. As a result people with epilepsy can suffer from serious cardiac arrhythmias, often precipitated by a seizure, which could contribute to their substantially increased risk of sudden death. Such deaths are termed Sudden Unexpected Death in EPilepsy (SUDEP), and this is a major clinical problem facing epilepsy patients, accounting for 17-38% of all epilepsy related deaths. Despite the high level of concern in the epilepsy community regarding cardiac dysfunction and SUDEP, and growing scientific attention into the problem, knowledge about the underlying causal mechanisms remains limited. Recent research from our laboratory has shown that heart function is detrimentally altered and the expression of ion channels critical for controlling cardiac rhythm, HCN channels, is reduced in animal models of chronic genetic and acquired epilepsy.

Understanding how chronic epilepsy results in cardiac dysfunction will allow us to develop intervention strategies to protect the heart from the adverse effects of chronic epilepsy, and thereby potentially reducing the risk of SUDEP.

Staff

  • Dr Pablo Casillas-Espinosa, Post-Doc
  • Emma Brain, Research Assistant
  • Joanne Huynh, Research Assistant
  • Pragati Sharma, PhD student  
  • Luke D'Arcy, Honours student
  • Bernard Le, Honours student

Collaborators

  • Associate Professor Chris Reid: Florey Neuroscience Institute
  • Professor Terry Snutch: University of British Columbia
  • Professor Margaret Morris: University of NSW
  • Professor Lea Delbridge: University of Melbourne
  • Professor Paul Pilowsky: University of Sydney
  • Dr Benoit Martin (U642 Inserm, Universit√© Rennes, France) and Dr Antoine Depaulis (Institut des Neurosciences, Grenoble, France)
  • Prof Colin Royse, Department of Surgery, The University of Melbourne

Funding

  • NHMRC project grant 2015-2018 How does chronic epilepsy result in cardiac electrophysiological dysfunction?

Research Opportunities

This research project is available to PhD students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Publications

  • Powell KL and O’Brien TJ (2015) In response: LQT, HCN, and epilepsy model. Epilepsia 56(11):1855-6.
  • Casillas-Espinosa PM, Hicks A, Jeffreys A, Snutch TP, O’Brien TJ and Powell KL (2015) Z944, a novel selective T-type calcium channel antagonist delays the progression of seizures in the amygdala kindling model. PLoS One 10(8):e0130012.
  • Powell KL, Tang H, Ng C, Guillemain I, Dieuset G, Onat F, Martin B, O’Brien TJ, Depaulis A and Jones NC (2014) Seizure expression, behavior and brain morphology differences in the Genetic Absence Epilepsy Rat from Strasbourg. Epilepsia. 55(12):1959-68.
  • Carack N, Zheng T, Ali I, Abdullah A, P, French C, Powell KL, Jones NC, van Raay L, Rind G, Onat F, and O'Brien TJ (2013) The effect of amygdala kindling on neuronal firing patterns in the lateral thalamus in the GAERS model of absence epilepsy. Epilepsia 55(5):654-665.
  • Powell KL, Jones NC, Kennard JTT, Ng C, Urmaliya V, Lau S, Ozturk E, Dezsi G, Megatia I, Delbridge LMD,  Pinault D,  Reid CA, White PJ, O’Brien TJ (2014) HCN channelopathy and cardiac electrophysiological dysfunction in genetic and acquired rat epilepsy models. Epilepsia 55(4):609-620.
  • Powell KL, Cain SM, Snutch TP, O’Brien TJ (2013) Low Threshold Calcium Channels as Targets for Novel Epilepsy Treatments. British Journal of Clinical Pharmacology 77(5):729-739.
  • Powell KL, Elms J, van Raay L, Dedeurwaerdere S, O’Brien TJ and Morris MJ (2013) Chronic valproate treatment increases NPY expression and decreases seizure expression in a genetic rat model of absence epilepsy. PLoS One 8(9): e73505.
  • Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O’Brien TJ, Jones NC (2013) Ethosuximide reduces epileptogenesis and behavioural comorbidity in the GAERS model of genetic generalised epilepsy. Epilepsia 54(4):635-43.
  • Casillas-Espinosa PM, Powell KL, O’Brien TJ (2012) Regulators of Synaptic transmission: Roles in the Pathogenesis and Treatment of Epilepsy.  Epilepsia 53 Suppl 9:41-58.
    Yuen TI, Morokoff A, Bjorksten A, D’Abaco G, Paradiso L, Finch S, Wong D, Reid CA,  Powell KL, Drummond K, Rosenthal MA, Kaye AH, O’Brien TJ (2012) Glutamate is associated with higher risk of seizures in gliomas. Neurology 79(9):883-9.
  • Tringham E, Powell KL,  Cain S, Kuplast K, Mezeyova J, Weerapura M, Eduljee C, Jiang X, Smith P, Morrison J, Jones NC, Braine E, Rind G, Parker D, Pajouhesh H, O’Brien TJ and Snutch TP (2012) Novel T-type calcium channel blockers attenuate thalamic burst firing and relieve absence seizures. Science Translational Medicine 4(121):121ra19.
  • Jones NC, O'Brien TJ and Powell KL (2011) Morphometric changes and molecular mechanisms in rat models of idiopathic generalized epilepsy with absence seizures. Neuroscience Letters 497(3):185-193.
  • Kennard JTT, Barmanray R, Sampurno S, Ozturk E, Reid CA, Paradiso L, D’Abaco GM, Kaye AH, Foote SJ, O’Brien TJ and Powell KL (2011) Stargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg. Neurobiology of Disease 42(1):48-54.
  • Powell KL, Cain SM, Ng C, Sirdesai S, David LS, Kyi M, Garcia E, Tyson JR, Reid CA, Bahlo M, Foote SJ, Snutch TP and O’Brien TJ (2009) A Cav3.2 T-Type Calcium Channel Point Mutation Has Splice Variant-Specific Effects on Function and Segregates with Seizure Expression in a Polygenic Rat Model of Absence Epilepsy. Journal of Neuroscience 29(2):371-780.
  • Monif M, Reid CA, Powell KL, Smart M, and Williams DA (2009) The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. Journal of Neuroscience 29(12):3781-3791.
  • Powell KL, Kyi M, Reid CA, Paradiso L, D’Abaco GM, Kaye AH, Foote SJ and O’Brien TJ (2008) Genetic Absence Epilepsy Rats from Strasbourg Have Increased Corticothalamic Expression of Stargazin. Neurobiology of Disease 31(2):261-265.  
  • Powell KL, Ng C, O’Brien TJ, Xu S, Williams DA, Foote SJ and Reid CA (2008) Decreases in HCN mRNA expression in the hippocampus after kindling and status epilepticus in adult rats. Epilepsia 49(10):1686-1695.