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Frances Jensen, M.D.

Professor of Neurology

Kirby Neurobiology Center
Children's Hospital
Center for Life Science Building
3 Blackfan Circle
Boston, MA 02115
Telephone: 617-919-2445
Fax: 617- 734-1646
Email: frances.jensen@childrens.harvard.edu
Lab Website: The Jensen Lab

The overall focus of this laboratory is to devise age-specific therapeutic strategies to prevent 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.

Clinically, the seizure incidence in infancy is higher than at any other time in life.  Neonatal seizures occur primarily in the term infant, and the most common cause of seizures is 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. When severe, seizures associated with hypoxic encephalopathy of the newborn can be 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 use a combination of in vivo and in vitro models of this injury in the developing rodent brain.  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.  This information has been used to devise therapeutic strategies for both pre and post treatment in perinatal hypoxic encephalopathy.  We currently are examining the potential clinical efficacy of two drugs that are in fact FDA approved for use for other indications and other age groups.  If final preclinical studies are successful, we hope to implement them based on a clinical trial at Children’s Hospital.

The second research emphasis is on injury to the premature brain.  Here, it appears that the white matter is selectively vulnerable to hypoxia/ischemia, and this results in PVL. 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.  We have extended our studies and found that a clinically available agent with glutamate blocking effects can also prevent the PVL-like damage to white matter, even when it is administered following the hypoxic/ischemic brain injury.  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.  We also plan to examine the potential clinical efficacy of this therapeutic strategy, with the hope of its translation to a clinical trial.  We hope that ongoing studies evaluating other mechanisms will produce additional therapeutic strategies for this disease process.

 

 

References:

  • Dzhala VL, Talos DM, Sdrulla DA,  Brumback AC, Mathews GC,  Benk TA, Delpire EJ, Jensen FE, Staley KJ.  (2005) NKCC1 ransporter facilitates seizures in the developing brain.  Nat Med 11:1207-1213.
  • Talos DM, Follett PL, Levada R, Folkerth R, Volpe JJ, Jensen FE.  (2006)  Developmental regulation of AMPA receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury: Part II.  Human Cerebral Cortex and White Matter. J Comp Neurol 497:61-77.
  • Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, Jensen FE, Kwiatkowski DJ.  (2007) A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival.  J Neurosci. May 23;27(21):5546-58.
  • Manning SM, Talos DM, Zhou C, Selip DB, Park HK, Park CJ, Volpe JJ, Jensen FE.  (2008) NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia.  J Neurosci. Jun 25;28(26):6670-8.
  • Rakhade, S*, Zhou, C, Aujla, P, Fishman, R, Sucher, N, Jensen, FE.  Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures.  J. Neurosci. 2008;28:7979-7990.
  • Aujla, P*, Fetell, M, Jensen, FE. Talampanel suppresses the acute and chronic effects of             seizures in a rodent neonatal seizure model.  Epilepsia, 2009 50 (4):694-701.
  • Jensen, FE.  Developmental factors in the pathogenesis of neonatal seizures.  J. Ped. Neurol. 2009;7:5-12.
  • Jensen, FE.  Post Traumatic Epilepsy:Treatable Epileptogenesis. Epilepsia,2009;50(S2):1-3.
  • Rakhade, S*, Jensen, FE.  Epileptogenesis in the Immature Brain: Emerging Mechanisms.  Nature Rev Neurol 2009; 5(7):380-91.

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