Scott Baraban, PhD

Professor
Department of Neurological Surgery
+1 415 476-9473

Epilepsy Associated with a Malformed Brain. A historical focus of our research, is on the development (and analysis) of animal models for specific childhood seizure disorders. Epileptic seizure disorders observed in children are often medically intractable and associated with some type of brain malformation. Our research is specifically designed to study rodents with malformations resembling those primarily seen in children. For example, a heterozygotic Lissencephaly-1 mouse (generated in the Wynshaw-Boris laboratory) mimics the haploinsufficiency associated with this pediatric epilepsy condition. The hippocampus in these mice shows clear signs of malformation including a severe loss of lamination and granule cell dispersion. In these mice, we have uncovered interesting deficits in the trafficking of excitatory synaptic vesicles and aberrant neurogenesis of newborn cells within a dysplastic granule cell layer. We are currently studying the functional consequences of these deficits in heterozygote and conditional Lis1 mutant mice, using visualized patch-clamp recording techniques and pharmacology.

Seizures and Epilepsy in Immature Zebrafish. Pediatric epilepsies are associated with developmental or cognitive co-morbidities and are only poorly controlled by available antiepileptic drugs (AEDs). Unfortunately, existing AED drug discovery programs are not designed to address this problem, as they are primarily based on acute or acquired seizures in adult rodents. Where our work seeks to shift current research in the epilepsy field is two-fold. First, by utilizing immature zebrafish models designed to mimic known single-gene mutations seen in children we are working to establish and characterize the first epileptic zebrafish. These studies focus on gene mutations for Angelman syndrome (ubiquitin E3 ligase), Dravet syndrome (Nav1.1), Benign Neonatal Familial Convulsions (KCNQ) and Lissencephaly (Lis-1). In vivo electrophysiological and behavioral assays developed in our laboratory are used to study epileptic phenotypes in these zebrafish; confocal imaging, in situ hybridization, micro-array and qPCR are also used. We recently showed that zebrafish can be used in a high-throughput screening strategy to identify lead compounds for intractable forms of pediatric epilepsy.

GABA Progenitor Cell Therapy for Epilepsy. GABAergic interneurons provide the primary source of inhibition in the central nervous system. Using human tissue derived from patients with intractable epilepsy (i.e., focal cortical dysplasia) and animal models lacking Dlx transcription factors necessary for the migration and differentiation of cortical interneurons (e.g., Dlx1 null mice), we have identified conditions where reduced interneuron density and loss of inhibition directly contributes to an epileptic phenotype. At the same time, working in close collaboration with Drs. John Rubenstein and Arturo Alvarez-Buylla, we have shown that embryonic neural progenitor cells from the medial ganglionic eminence (MGE) can be used to generate new and functional interneurons when grafted into a host brain. We recently showed that these MGE progenitor cells effectively eliminate spontaneous electrographic seizure activity following transplantation into mouse models of epilepsy. Further development of this cell-based interneuron strategy is currently underway.

Research Summary: 
Neurobiology of Epilepsy

Websites

Publications: 

Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome.

Brain : a journal of neurology

Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC

Advancing epilepsy treatment through personalized genetic zebrafish models.

Progress in brain research

Griffin A, Krasniak C, Baraban SC

Altered Glycolysis and Mitochondrial Respiration in a Zebrafish Model of Dravet Syndrome.

eNeuro

Kumar MG, Rowley S, Fulton R, Dinday MT, Baraban SC, Patel M

Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.

PloS one

Grone BP, Marchese M, Hamling KR, Kumar MG, Krasniak CS, Sicca F, Santorelli FM, Patel M, Baraban SC

Interneuron Transplantation as a Treatment for Epilepsy.

Cold Spring Harbor perspectives in medicine

Hunt RF, Baraban SC

NPAS1 represses the generation of specific subtypes of cortical interneurons.

Neuron

Stanco A, Pla R, Vogt D, Chen Y, Mandal S, Walker J, Hunt RF, Lindtner S, Erdman CA, Pieper AA, Hamilton SP, Xu D, Baraban SC, Rubenstein JL

14-3-3e and ? regulate neurogenesis and differentiation of neuronal progenitor cells in the developing brain.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Toyo-oka K, Wachi T, Hunt RF, Baraban SC, Taya S, Ramshaw H, Kaibuchi K, Schwarz QP, Lopez AF, Wynshaw-Boris A

GABAB receptors in maintenance of neocortical circuit function.

Experimental neurology

Sebe JY, Looke-Stewart E, Baraban SC

Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position.

Neuron

Vogt D, Hunt RF, Mandal S, Sandberg M, Silberberg SN, Nagasawa T, Yang Z, Baraban SC, Rubenstein JL

Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain.

Neuron

Silbereis JC, Nobuta H, Tsai HH, Heine VM, McKinsey GL, Meijer DH, Howard MA, Petryniak MA, Potter GB, Alberta JA, Baraban SC, Stiles CD, Rubenstein JL, Rowitch DH

What new modeling approaches will help us identify promising drug treatments?

Advances in experimental medicine and biology

Baraban SC, Löscher W

Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo.

Proceedings of the National Academy of Sciences of the United States of America

Howard MA, Rubenstein JL, Baraban SC

Neocortical integration of transplanted GABA progenitor cells from wild type and GABA(B) receptor knockout mouse donors.

Neuroscience letters

Sebe JY, Looke-Stewart E, Dinday MT, Alvarez-Buylla A, Baraban SC

GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior.

Nature neuroscience

Hunt RF, Girskis KM, Rubenstein JL, Alvarez-Buylla A, Baraban SC

Use of "MGE enhancers" for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons.

PloS one

Chen YJ, Vogt D, Wang Y, Visel A, Silberberg SN, Nicholas CR, Danjo T, Pollack JL, Pennacchio LA, Anderson S, Sasai Y, Baraban SC, Kriegstein AR, Alvarez-Buylla A, Rubenstein JL

Forebrain electrophysiological recording in larval zebrafish.

Journal of visualized experiments : JoVE

Baraban SC

The devil is in the details: stem cells for the treatment of epilepsy.

Epilepsy currents / American Epilepsy Society

Hunt RF, Baraban SC

ALLN rescues an in vitro excitatory synaptic transmission deficit in Lis1 mutant mice.

Journal of neurophysiology

Sebe JY, Bershteyn M, Hirotsune S, Wynshaw-Boris A, Baraban SC

Intrinsically determined cell death of developing cortical interneurons.

Nature

Southwell DG, Paredes MF, Galvao RP, Jones DL, Froemke RC, Sebe JY, Alfaro-Cervello C, Tang Y, Garcia-Verdugo JM, Rubenstein JL, Baraban SC, Alvarez-Buylla A

LIS1 deficiency promotes dysfunctional synaptic integration of granule cells generated in the developing and adult dentate gyrus.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Hunt RF, Dinday MT, Hindle-Katel W, Baraban SC

Familial cortical myoclonus with a mutation in NOL3.

Annals of neurology

Russell JF, Steckley JL, Coppola G, Hahn AF, Howard MA, Kornberg Z, Huang A, Mirsattari SM, Merriman B, Klein E, Choi M, Lee HY, Kirk A, Nelson-Williams C, Gibson G, Baraban SC, Lifton RP, Geschwind DH, Fu YH, Ptácek LJ

Expression and function of KCNQ channels in larval zebrafish.

Developmental neurobiology

Chege SW, Hortopan GA, T Dinday M, Baraban SC

Impaired neural development in a zebrafish model for Lowe syndrome.

Human molecular genetics

Ramirez IB, Pietka G, Jones DR, Divecha N, Alia A, Baraban SC, Hurlstone AF, Lowe M

Aberrant expression of genes necessary for neuronal development and Notch signaling in an epileptic mind bomb zebrafish.

Developmental dynamics : an official publication of the American Association of Anatomists

Hortopan GA, Baraban SC

Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons.

Journal of neurophysiology

Jones DL, Howard MA, Stanco A, Rubenstein JL, Baraban SC

The promise of an interneuron-based cell therapy for epilepsy.

Developmental neurobiology

Sebe JY, Baraban SC

Spontaneous seizures and altered gene expression in GABA signaling pathways in a mind bomb mutant zebrafish.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Hortopan GA, Dinday MT, Baraban SC

Robust tonic GABA currents can inhibit cell firing in mouse newborn neocortical pyramidal cells.

The European journal of neuroscience

Sebe JY, Looke-Stewart EC, Estrada RC, Baraban SC

Dlx5 and Dlx6 regulate the development of parvalbumin-expressing cortical interneurons.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Wang Y, Dye CA, Sohal V, Long JE, Estrada RC, Roztocil T, Lufkin T, Deisseroth K, Baraban SC, Rubenstein JL

Zebrafish as a model for studying genetic aspects of epilepsy.

Disease models & mechanisms

Hortopan GA, Dinday MT, Baraban SC

Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice.

Annals of neurology

Greenwood JS, Wang Y, Estrada RC, Ackerman L, Ohara PT, Baraban SC

Basic mechanisms of MCD in animal models.

Epileptic disorders : international epilepsy journal with videotape

Battaglia G, Becker AJ, LoTurco J, Represa A, Baraban SC, Roper SN, Vezzani A

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice.

Proceedings of the National Academy of Sciences of the United States of America

Baraban SC, Southwell DG, Estrada RC, Jones DL, Sebe JY, Alfaro-Cervello C, García-Verdugo JM, Rubenstein JL, Alvarez-Buylla A

Developing cell transplantation for temporal lobe epilepsy.

Neurosurgical focus

Richardson RM, Barbaro NM, Alvarez-Buylla A, Baraban SC

A large-scale mutagenesis screen to identify seizure-resistant zebrafish.

Epilepsia

Baraban SC, Dinday MT, Castro PA, Chege S, Guyenet S, Taylor MR

Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1.

Annals of neurology

Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC

Stromal-derived factor-1 (CXCL12) regulates laminar position of Cajal-Retzius cells in normal and dysplastic brains.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Paredes MF, Li G, Berger O, Baraban SC, Pleasure SJ

Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Alvarez-Dolado M, Calcagnotto ME, Karkar KM, Southwell DG, Jones-Davis DM, Estrada RC, Rubenstein JL, Alvarez-Buylla A, Baraban SC

A role for the mTOR pathway in surface expression of AMPA receptors.

Neuroscience letters

Wang Y, Barbaro MF, Baraban SC

Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Calcagnotto ME, Paredes MF, Tihan T, Barbaro NM, Baraban SC

Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy.

Nature neuroscience

Cobos I, Calcagnotto ME, Vilaythong AJ, Thwin MT, Noebels JL, Baraban SC, Rubenstein JL

Pain without gain (of function): sodium channel dysfunction in epilepsy.

Epilepsy currents / American Epilepsy Society

Cooper EC, Baraban SC

Target-specific neuropeptide Y-ergic synaptic inhibition and its network consequences within the mammalian thalamus.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Sun QQ, Baraban SC, Prince DA, Huguenard JR

Heterotopic neurons with altered inhibitory synaptic function in an animal model of malformation-associated epilepsy.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Calcagnotto ME, Paredes MF, Baraban SC

A review of gene expression patterns in the malformed brain.

Molecular neurobiology

Paredes MF, Baraban SC

Epilepsy Research Takes Flight.

Epilepsy currents

Baraban SC

Y5 receptors mediate neuropeptide Y actions at excitatory synapses in area CA3 of the mouse hippocampus.

Journal of neurophysiology

Guo H, Castro PA, Palmiter RD, Baraban SC

Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Castro PA, Cooper EC, Lowenstein DH, Baraban SC

Hippocampal dysplasia in rats exposed to cocaine in utero.

Brain research. Developmental brain research

Baraban SC, Wenzel HJ, Castro PA, Schwartzkroin PA

Role of the Y5 neuropeptide Y receptor in limbic seizures.

Proceedings of the National Academy of Sciences of the United States of America

Marsh DJ, Baraban SC, Hollopeter G, Palmiter RD

Cortical malformations and epilepsy: new insights from animal models.

Epilepsia

Chevassus-au-Louis N, Baraban SC, Gaïarsa JL, Ben-Ari Y

Osmolarity, ionic flux, and changes in brain excitability.

Epilepsy research

Schwartzkroin PA, Baraban SC, Hochman DW

Life without neuropeptide Y.

Recent progress in hormone research

Palmiter RD, Erickson JC, Hollopeter G, Baraban SC, Schwartz MW

Neuropeptide Y and limbic seizures.

Reviews in the neurosciences

Baraban SC

Knock-out mice reveal a critical antiepileptic role for neuropeptide Y.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Baraban SC, Hollopeter G, Erickson JC, Schwartzkroin PA, Palmiter RD

Evidence for increased seizure susceptibility in rats exposed to cocaine in utero.

Brain research. Developmental brain research

Baraban SC, McCarthy EB, Schwartzkroin PA

Osmolarity modulates K+ channel function on rat hippocampal interneurons but not CA1 pyramidal neurons.

The Journal of physiology

Baraban SC, Bellingham MC, Berger AJ, Schwartzkroin PA

Role of medulla oblongata in generation of sympathetic and vagal outflows.

Progress in brain research

Guyenet PG, Koshiya N, Huangfu D, Baraban SC, Stornetta RL, Li YW

Dissociation of synchronization and excitability in furosemide blockade of epileptiform activity.

Science (New York, N.Y.)

Hochman DW, Baraban SC, Owens JW, Schwartzkroin PA

Kappa opioid receptor-mediated suppression of voltage-activated potassium current in a catecholaminergic neuronal cell line.

The Journal of pharmacology and experimental therapeutics

Baraban SC, Lothman EW, Lee A, Guyenet PG

Respiratory control of sympathetic nerve activity during naloxone-precipitated morphine withdrawal in rats.

The Journal of pharmacology and experimental therapeutics

Baraban SC, Stornetta RL, Guyenet PG