Description of Research Expertise:
The primary focus of my research is to investigate pathophysiological mechanisms of epilepsy and stroke, and secondary effects on synaptic plasticity. A secondary goal is to elucidate age-dependent differences in such mechanisms, and to examine the interactions between brain development, excitotoxic brain injury, epilepsy and cognition. Neurotransmitter receptors are developmentally regulated, and we have specifically demonstrated critical roles of these receptors, as well as their upstream modulators and downstream effectors, in neuronal and glial cells that are unique to the immature, implying age-specific disease mechanisms. The overall aim is to develop new targets based on novel mechanisms for the treatment of epilepsy, stroke, and autism.
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Summary of major research findings:
1. Establishment of in vivo and in vitro rodent models of neonatal seizures and perinatal hypoxic/ischemic cerebral injury for examination of cellular and molecular factors influencing age-specific susceptibility, epileptogenicity, and cellular injury.
2. Demonstration that calcium-permeable AMPA receptors are constitutively expressed on neurons and glia in developing rodent and human hippocampus and neocortex, and that these are critical to the mechanisms of seizures and ischemic injury in the developing brain.
3. First demonstration that AMPA receptor antagonists selectively block seizures in the immature brain, but not in the adult. Additional demonstration that the clinically available drugs topiramate and talampanel attenuate AMPA receptor currents and suppress neonatal seizures and stroke, including periventricular leukomalacia, in rat models.
4. Elucidation of novel calcium-mediated signaling pathways downstream from the AMPA receptor that play critical roles in the pathogenesis of epilepsy in the immature brain, and preclinical efficacy of preventative or rescue treatment in rodent models. Specific pathways include those mediated by early post-translational changes to glutamate and GABA receptors that increase synaptic excitability. First demonstration that AMPA receptor antagonists including NBQX, topiramate and talampanel can reverse these changes when administered as post-seizure treatment, and prevent long term changes.
5. Identification of novel phosphorylation sites Ser 831 and Ser 845 on the GluR1 subunit of the AMPA receptor that are required for the epileptogenic effect of early life seizures, suggesting a novel mechanism for epileptogenesis.
6. Development of novel antiepileptic and neuroprotective strategies that are permissive of neuronal plasticity and long term potentiation. These include the NMDA receptor redox site modulator pyrroloquinoline quinone, and the use-dependent, uncompetitive NMDA blocker memantine as highly protective in vivo and in vitro stroke models, without significant neurocognitive effects.
7. Identified parallel patterns of relative underexpression of the KCC2 chloride transporter versus NKCC1 transporter in human and rodent perinatal cortex during developmental period when GABA receptor agonists are ineffective as antiepileptic agents. This result is the first to strongly implicate the presence of depolarizing GABA receptors in human neonates. This date provided the preclinical target validation that was critical for translation of the use of the NKCC1 inhibitor bumetanide in an FDA approved NIH-funded ongoing clinical trial at CHB and Partners – Phase I/II safety PK trial in neonatal seizures.
8. Elucidation of abnormal patterns of glutamate and GABA receptors,in human tissue from malformations of cortical development, such as Tuberous Sclerosis, and that these changes are associated with epileptic foci. These results are presently under evaluation with respect to the generation of new clinical treatment trials.
9. Demonstration of convergence of signaling deficits in early life seizures and autism. Alterations in canonical autism-related pathways, including mTOR, FMRP and MeCP2, occur secondary to seizures in the developing brain.
In summary, the emphasis of this translational research program is to identify age-specific mechanisms of brain injury at the cellular level using a variety of in vivo and in vitro techniques, and to use this information to explore and devise experimental therapeutic strategies with clinical potential. Several therapeutic strategies developed in the laboratory are being considered for clinical development. We have established IRBs that have created a repository of human tissue from surgical specimens and autopsy material, and routinely obtain brain tissue directly from surgery for electrophysiological investigation.
Jantzie Lauren L, Talos Delia M, Jackson Michele C, Park Hyun-Kyung, Graham Dionne A, Lechpammer Mirna, Folkerth Rebecca D, Volpe Joseph J: Developmental Expression of N-Methyl-D-Aspartate (NMDA) Receptor Subunits in Human White and Gray Matter: Potential Mechanism of Increased Vulnerability in the Immature Brain. Cerebral cortex (New York, N.Y. : 1991) : 2013.
Engel J Jr, Pitkänen A, Loeb JA, Edward Dudek F, Bertram EH 3rd, Cole AJ, Moshé SL, Wiebe S, Jensen FE, Mody I, Nehlig A: Epilepsy Biomarkers Epilepsia : 2013.
Pitkänen Asla, Nehlig Astrid, Brooks-Kayal Amy R, Dudek F Edward, Friedman Daniel, Galanopoulou Aristea S, Jensen Frances E, Kaminski Rafal M, Kapur Jaideep, Klitgaard Henrik, Löscher Wolfgang, Mody Istvan: Issues related to development of antiepileptogenic therapies. Epilepsia 54 Suppl 4 : 35-43,2013.
Brooks-Kayal Amy R, Bath Kevin G, Berg Anne T, Galanopoulou Aristea S, Holmes Gregory L, Jensen Frances E, Kanner Andres M, O'Brien Terence J, Whittemore Vicky H, Winawer Melodie R, Patel Manisha: Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 54 Suppl 4 : 44-60,2013.
Wintermark Pia, Lechpammer Mirna, Warfield Simon K, Kosaras Bela, Takeoka Masanori, Poduri Annapurna, Madsen Joseph R, Bergin Ann M, Whalen Stephen: Perfusion Imaging of Focal Cortical Dysplasia Using Arterial Spin Labeling: Correlation With Histopathological Vascular Density. Journal of child neurology : 2013.
Ryan T. Cleary, Hongyu Sun, Thanhthao Huynh, Simon M. Manning, Yijun Li, Alexander Rotenberg, Delia M. Talos, Kristopher T. Kahle, Michele Jackson, Sanjay N. Rakhade, Gerard Berry: Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures PLOS ONE : 10.1371/journal.pone.0057148,2013.
Jacobs Margaret: Introduction to institute of medicine report: epilepsy across the spectrum: promoting health and understanding. Epilepsy currents / American Epilepsy Society 12 (6): 243-4,2012.
Kowbow K, Auvin S, Jensen F, Loscher W, Mody I, Potschka H, Prince D, Sierra A, Simonato M, Pitkanen A, Nehlig A: Finding a better drug for epilepsy: Antiepileptogenesis Targets Epilepsia : 2012.
Zhou C, Lippman Bell JJ, Sun H: Learning Through Silence: Amping up Cognition After Neonatal Hypoxic Seizures Through AMPA Receptor Inhibition Journal of Neuroscience : 2012.