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
Rachel White, Ph.D.
Research Associate Scientist
University of California, San Diego: BS Anatomy, Physiology and Neuroscience
University of Pennsylvania, School of Medicine: Ph.D. Neuroscience
Sarah Gourmaud, PhD
Pierre and Marie Curie University, Paris, France, MA 2011 Cell Biology
Paris Diderot University, Paris, France, PhD 2014 Neuroscience
University of Pennsylvania, Neurology
My translational research focuses on the relationship between epilepsy and Alzheimer’s disease (AD). I am evaluating markers of epileptogenesis in both AD patients and AD mice model and studying the effect of seizures on AD neuropathology. I am also conducting pre-clinical therapeutic trials in AD mice. In parallel, I am examining human temporal lobe epilepsy brain tissue for AD pathology, which may represent a risk factor for epilepsy-associated cognitive impairment and even dementia.
I have a neuroscience background, with a specialty in AD pathophysiology. During my PhD, I studied the potential role of a Mitogen-activated protein kinase as a diagnostic biomarker and therapeutic target of AD using both human patients and AD mice biological samples.
Pharmacology Graduate Student
Keisuke Hashimoto, Ph.D.
Neuroscience PhD Candidate
University of Pennsylvania
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) levels, 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.
Evan L. Honig
Undergraduate Research Assistant
University of Pennsylvania, College of Arts and Sciences, B.A. May 2018
major - Biological Basis of Behavior; minor - Chemistry
Since June 2015, I have worked in the Jensen Lab, where I examine the role of endocannabinoid and GABAergic systems--modulators of excitation/inhibition balance in the brain--in a mouse model of Fragile X Syndrome (FXS). FXS is the most prevalent form of heritable intellectual disability comorbid with seizures. I also study the effects of early-life seizures on excitatory and inhibitory markers during auditory cortex development--an area vital for language acquisition. Results from these projects will hopefully enable future development of targeted therapeutic interventions that may suppress seizures in early-life epilepsy and FXS, both of which lack currently effective treatments.