The major focus of my laboratory is on developing new age-specific therapies for epilepsy and its comorbidities. We specifically focus on forms of epilepsy that affect the infant and early childhood brain, and have extensive expertise in investigations of human tissue as well as rat and mouse models of early life epilepsy. Our interests have been on hypoxic/ischemic injury and seizures in the perinatal and young postnatal brain. My lab has published expertise in cellular and regional alterations in synaptic proteins and signaling pathways using whole animal, human tissue, and in vitro brain slices and cell cultures. Almost 20 years ago we showed that hypoxia can induce seizures in the neonatal brain and this increased network excitability in adulthood; over the years we have worked to show that AMPARs are involved in this epileptogenesis and that spontaneous seizures are increased in adulthood, confirming this as a model of epileptogenesis.
We also discovered if seizures occur during the critical period of early brain development, synaptic plasticity mechanisms are dysregulated to produce epilepsy–induced synaptic potentiation, and importantly in addition to impairing Hebbian plasticity, there is also an autistic–like behavioral phenotype. Hence our interest in understanding the interaction in epilepsy and autism/neurodevelopmental delay. Along these lines, we discovered alterations of the mTOR pathway following early life seizures and injury in the wild type rat brain, and a protective role for rapamycin in preventing long term epilepsy and autistic–like behavior.
We now extend our findings to the related Fragile X mental retardation protein (FMRP), as another possible therapeutic target for seizure induced epilepsy and neurodevelopmental deficits. We are uniquely positioned to conduct basic cellular and molecular mechanistic studies to reveal therapeutic targets, as well as perform proof–of–concept studies in animal models of diseases, especially epilepsy and hypoxic/ischemic brain injury. We have established similarities in epilepsy–induced proteins in animal models as well as human brain biopsy material, and are currently evaluating these for their potential as biomarkers. We also investigate factors that may contribute to cognitive impairment in epilepsy, and especially how mechanisms of epileptogenesis may overlap with those important for synaptic plasticity, learning and memory. In the immature brain we study an important cognitive disorder, autism and its interaction with epilepsy. In addition, we apply cellular and molecular techniques to validate targets in post mortem as well as surgical biopsy human brain material.
Finally, I am actively involved in the translation of discovery to early human trials, and collaborate with my clinical colleagues to expedite human–based studies. For example, the first in–human trials of bumetanide as a treatment for neonatal seizures have begun, translating discoveries from my laboratory into the first such trial of a novel, age–specific anti–seizure medication. Finally, our parallel work with bumetanide in a neonatal seizure model, along with work by many other laboratories, has resulted in a phase I/II clinical trial. Given our hospital university setting, we hope that we can translate our findings to future human therapeutic trials.