Epilepsy

Epilepsy is a recurrent seizure syndrome caused by pathological synchronized firing of subpopulations of CNS neurons and is one of the most common neurological disorders, affecting approximately 3 million people within the US alone.  Over 100 known Mendelian diseases include epilepsy as part of the neurological manifestation.  Although epilepsy can be caused by many factors including fever, ischemic brain insults (stroke), traumatic brain injury or cancer, more than 40% of patients with epilepsy have been suggested to have a genetic component that contributes to the etiology.  To identify neuronal dysfunctions that cause epilepsy, we have conducted behavioral screens for temperature-sensitive (TS) paralytic mutations induced by EMS that result in seizures. To date, 79 seizure-inducing mutations that define 27 complementation groups have been identified in large-scale screens of homozygous viable lines generated in the lab. We find that increasing neuronal activity drives overproliferation of synaptic connections, indicating activity-dependent rewiring occurs in Drosophila as observed in mammalian epilepsy models. To analyze transcriptional recoding during altered neuronal activity, we performed genome-wide DNA microarray analysis following multiple seizure induction and recovery paradigms in Drosophila mutants with acute or chronic alterations in neuronal activity.  Approximately 250 genes implicated in cell adhesion, membrane excitability, and cellular signaling are differentially regulated, identifying a collection of activity-regulated transcripts that may link changes in neuronal firing patterns to transcription-dependent modulation of brain function. RNAi-mediated disruption or overexpression of several of these transcripts alters synaptic growth, suggesting an important role for transcriptional regulation in activity-dependent synaptic rewiring.  These 250 activity-regulated transcripts represent exciting candidate genes that may regulate synaptic morphology and synaptic transmission, and will form the basis for new studies into how the brain responds to enhanced activity that occurs during plasticity, and in an exaggerated form during epilepsy.