Frances Jensen, MD, FACP
Professor and Chair
Smith College, Northampton, MA A.B. 1978 Psychology
Cornell University Medical College, NY, NY M.D. 1983 Medicine
Harvard University M.A. (Hon) 2007 Medicine
The overall focus of the Jensen laboratory is to devise age-specific therapeutic strategies to prevent epilepsy and brain injury in perinatal period. We focus on understanding the molecular and cellular pathophysiology of 2 highly prevalent forms of injury: hypoxic encephalopathy and seizures in the full term infant and hypoxic/ischemic injury to the white matter (periventricular leukomalacia, PVL) in the premature infant. Our overall interest is on the interaction between brain development and injury. We have a specific interest in the role of glutamate receptor maturation in excitotoxicity and epileptogenesis in the immature brain. Finally, we also study the long term consequences of these processes on later life cognition and behavior.
Clinically, the seizure incidence in infancy is higher than at any other time in life, with the most common cause being lack of oxygen (hypoxia) and/or blood flow (ischemia), due to birth asphyxia, insufficient lung function, and infection, among other causes. Some infants go on to develop neurocognitive deficits, mental retardation, and/or epilepsy. In many cases, these newborn infants are refractory to conventional medications that are effective in older children and adults. The age-dependency and the lack of response to conventional medications suggest that this injury might have mechanisms different from those in a similarly affected mature brain. Our work thus far has identified a critical role of a specific neurotransmitter receptor, the AMPA subtype of glutamate receptors, in the vulnerability to and subsequent development of epilepsy. We have also shown that the presence of depolarizing GABA receptors and high levels of expression of the Cl cotransporter NKCC1 uniquely contribute to epilepsy in the developing brain. We use a combination of in vivo and in vitro models to perform translational studies. We are examining the sequence of changes that take place in the perinatal brain following an early life seizure, and how these can result in abnormalities of brain development and epilepsy. We currently have a Phase I/II study underway in human neonatal seizures based on our work (clinicaltrials.gov/ NCT00830531).
The second research emphasis is on injury to the premature brain. PVL is the major antecedent to cerebral palsy, and to date no specific treatment exists. PVL occurs in premature infants that have respiratory distress, hypotension, sepsis and other complication of prematurity. Given the improved medical techniques, the number of infants born between 25-27 weeks and less than 1500 grams in birthweight is rising, yet these infants are those with the greatest risk of such complications. We have used in vivo and in vitro rodent models of injury to the primary cell type in the white matter, the oligodendrocyte. We and collaborators have found that the immature forms of oligodendrocytes that are present in the premature brain appear to be more sensitive to hypoxia/ischemia than mature forms that are present in brains of individuals of older ages. We examined the mechanism of toxicity, and found that these cells transiently express glutamate receptors during the window of vulnerability to hypoxia/ischemia. Subsequent studies showed that pharmacologic blockade of glutamate receptors on oligodendrocytes prevented the PVL-like injury in rodent models. Further studies on human autopsy tissue have shown that these glutamate receptors are likely present in the human white matter brain during the window of vulnerability to PVL, increasing the clinical relevance of our findings in our animal models. These ongoing studies evaluating other mechanisms are designed to produce additional therapeutic strategies for this disease process.
Finally, a recent emphasis in the lab relates to cognitive consequences of epilepsy in the developing brain, but also at any age. Approximately 50% of people with epilepsy have cognitive or psychiatric deficits. We have shown that multiple pathways involved in activity-dependent synaptic plasticity and learning are also dysregulated by epileptic seizures. In the developing brain, this can interfere with normal critical period mechanisms, and result in abnormal networks. Certain pathways implicated in autism syndromes are affected by early life seizures, and indeed our animal models reveal autistic-like behavior and impaired critical period plasticity following early seizures. We also show that seizures can occlude normal Hebbian activity dependent mechanisms such as LTP and LTD. Other studies are identifying that homeostatic plasticity is also inhibited by seizures, enhancing epileptogenesis. These mechanistic studies are identifying potential intervention points to prevent the cognitive and behavioral consequences of epilepsy.
Department of Neurology
Perelman School of Medicine, University of Pennsylvania
3400 Spruce Street, 3rd Floor Gates Building
Philadelphia, PA 19104-4283
Phone: (215) 662-3360
Fax: (215) 662-3362
Jocelyn J Lippman-Bell, PhD
Boston University BA 05/00 Biology: Neuroscience
Brown University PhD 05/08 Neuroscience
Children’s Hospital Boston/Harvard Med School 11/12 Neurology/epilepsy
University of Pennsylvania Neurology
I have a broad neuroscience background, with a specialty in cellular neuroscience techniques, especially quantitative cellular imaging. For my graduate work, I examined the development of neuron/glial relationships at cerebellar synapses using molecular techniques and single and multi-photon imaging, predominantly dendritic spine and glial process imaging in live slices and fixed, immunostained sections. My postdoctoral work has allowed me to use these techniques, along with calcium imaging and western blotting, to examine changes in synapses and neuronal signaling following neonatal hypoxia-induced seizures.
Temple University BA Biology
As Lab Manager I ensure that our lab maintains compliance with all regulatory agencies at the Institutional (Penn IACUC and Penn/CHOP IRB) and governmental (NIH) level, actively support the grant writing and submission process, procure lab supplies and equipment, and maintain a safe well organized environment for our lab members and visitors. Aside from administrative responsibilities I provide research support for studies apposite to epilepsy and age-specific therapeutic strategies to prevent epilepsy and brain injury in perinatal period.
Drexel University BS Biology: Biochemistry and Genetics
I study new age-specific therapies, and the role of altered neuronal and glial function in epilepsy. I assese the changes in cellular and regional synaptic proteins and signaling pathways in both animal and human tissue, and also explore the expression patterns of neurotransmitter receptors in the brain through immunocytochemistry and western blot techniques.
University of Pennsylvania BA Biological Basis of Behavior