The maturation of GABAA receptor-mediated signaling from depolarizing to inhibitory is an age-related process controlled by cation chloride cotransporters, such as KCC2. As a result, GABA exerts dual functions, being an important neurotrophic factor during early development and the principal inhibitory neurotransmitter of the mature central nervous system. In our laboratory we have been investigating the age and gender specific mechanisms through which early life stressors and seizures may disrupt the normal patterns of brain development, by disrupting the neurotrophic effects of GABA. We are also studying methods to reverse these adverse processes. Furthermore, we are very interested in understanding how epileptogenesis proceeds in the developing brain and what is the specific role of GABAA receptors in this process.
To better understand the pathophysiology and design better methods to treat catastrophic early life epilepsies, we are developing and studying new models of early life epilepsy. These include models of symptomatic infantile spasms that recapitulate most of the features of the human condition. Several projects are under way to (a) elucidate the pathophysiology of infantile spasms, and (b) conduct preclinical trials to find better treatments for spasms and the associated comorbidities. Our studies have provided preclinical evidence for new potential treatments with disease modifying properties for these early life epileptic encephalopathies, such as mTOR inhibitor, carisbamate and a new vigabatrin analog.
Post-traumatic epilepsy is a common consequence of traumatic brain injury leading to high morbidity and morbidity. Our lab is participating in an international multicenter preclinical consortium, EpiBioS4Rx, leading efforts to develop better therapies for post-traumatic epilepsy. We use a rodent model of traumatic brain injury to identify targets and test for better therapies, through a combination of expression studies, in vivo behavioral and electrophysiologic monitoring and therapy screening to identify antiepileptogenic compounds. Furthermore, through a separate project, we are looking into factors predicting epilepsy and behavioral outcomes after traumatic brain injury.
Genetic etiologies are often identified in patients with epilepsies. Our lab has been investigating genes involved in lissencephaly associated epilepsies and developmental disorders as well as Rett syndrome which is due to MeCP2 gene mutations. Through the use of mouse models we have been investigating genotype-phenotype correlations and mechanisms involved with the ultimate goal of testing therapies.
Students interested in these projects will gain exposure to a variety of in vivo and in vitro techniques that combine molecular biology, in vivo and in vitro electrophysiology, histological, and behavioral studies and will be involved in projects with direct translational relevance to the clinical practice, i.e. identification of novel therapies.