Programmed cell death and neurodegeneration in the mammalian cerebral cortex and hippocampus; stem cell therapy for epilepsy; STEP and control of seizures.

Current work in my laboratory examines how neuronal cell death and neurogenesis are regulated in the embryonic and adult mammalian brain. Our group studies these processes during normal development, in developmental disorders, and in epilepsy. Our focus is on both endogenous neural precursors in the fetal brain and on mouse and human ES-derived neural stem cells.

Role of DNA repair in neuronal cell death in the cerebral cortex and hippocampus.  We study mice deficient in the Non-homologous end-joining pathway (NHEJ), a mechanisms for DNA double strand break (DSB) repair, to understand how DNA damage triggers apoptosis. We showed that Ku70 is required for neuronal survival, as neural stem cells make the transition to becoming postmitotic neurons. NHEJ in developing neurons may serve to repair DSBs incurred as young neuroblasts differentiate, migrate, or establish synaptic connections. Current work is identifying the sources of DSBs and signals, including Bax and p53, that trigger cell death. We have also found a role for NHEJ in maintenance of adult neural stem cells in the adult subventricular zone and dentate gyrus, two regions of on-going neurogenesis in the adult brain. We utilize a variety of cutting-edge techniques, including in utero electroporation, RNA interference, primary cell cultures, neurosphere cultures, immunohistochemistry, and BrdU birthdating.

Epilepsy. In human mesial temporal lobe epilepsy (TLE) and in rodent models of TLE, status epilepticus (a sustained seizure) may trigger neurodegeneration in the hippocampus and related limbic circuits, as well as mossy fiber sprouting and other plastic changes. We have shown that DNA-PKcs deficient mice exhibit an enhanced neurodegenerative response to kainic acid induced seizures, suggesting that NHEJ protects mature neurons from excitotoxic damage. We have also demonstrated that kainic acid induced excitotoxic cell death activates the DNA repair enzyme PARP within injured neurons. My lab uses several distinct chemoconvulsant models of TLE (pilocarpine, kainic acid) to study neuronal repair, neuroprotection and excitotoxic cell death. Seizures are studied behaviorally using direct observations, video recordings, and electroencephalography (EEG). We have on-going collaborations with labs at Wesleyan, Yale, and Ohio State for our epilepsy work.

ES-derived GABAergic neurons for neuronal repair and seizure control. We have shown that intrahippocampal grafts of murine and human ES cell-derived neural stem cells survive, migrate, and integrate into the dentate gyrus of mice following kainic acid-induced seizures. Currently, we making transplants into the adult hippocampus of mice after status epilepticus to test whether ES-derived neural stem cell grafts can limit or reduce seizures. We aim to generate GABAergic precursors from mouse and human ES cell lines for these studies.

Striatal Enriched Phosphatase (STEP), Seizure thresholds, and Excitotoxcity. The mechanisms leading to recurrent seizures and epilepsy are not well understood. Recent work in the lab has identified increased seizure thresholds in mice deficient in STEP, an important protein tyrosine phosphatase that regulates NMDA receptors and extracellular regulated kinase (ERK). Both of these proteins play critical roles in neuronal survival and excitability. Studies are exploring the mechanisms for seizure resistance in STEP knockout mice, hippocampal slices, and neuronal cell cultures derived from the hippocampus of these mice.
 

Research in Naegele's Laboratory of Developmental Neurobiology is funded by grants from the McKnight Foundation (http://www.mcknight.org/neuroscience/), the Connecticut Stem Cell Research Program (http://www.ct.gov/dph/cwp/view.asp?a=3142&q=389700&dphNav_GID=1825&dphNav=|),  FRAXA  (http://www.fraxa.org/), and the American Epilepsy Society (http://www.aesnet.org/).

• Janice Naegele's  Publications
• Courses taught by Dr. Naegele: BIOL/NSB 345, BIOL/NSB 213
• Naegele Lab Photos