Candidate and Environment: This candidate has completed extensive neuroscience training at Harvard and MIT. Beth Israel Neurology has provided an independent laboratory and start-up funds. The candidate's K08 funding ends in 11/05 and he needs continued salary support to protect his research time. This Award would enable him to obtain the preliminary data necessary to obtain an R01 grant. His long term goal is to continue his full-time biomedical research career at Beth Israel/ Harvard Medical School. In the career development plan, the candidate proposes to apply his training and experience to the study of epilepsy. Research Project Summary: The molecular mechanisms in the brain that underlie the spike-and-wave seizures of childhood absence epilepsy (CAE) have long been debated. This proposal uses new bacteriophage P1-derived Cre/loxP recombination techniques to target absence epilepsy gene mutations to specific neuron subtypes in the murine brain. Childhood absence epilepsy-associated mutations were recently discovered in the T-type calcium channel Cav3.2 gene. The project's hypothesis is that Cav3.2 mutations alter the firing properties of specific neuron subtypes to cause the characteristic 3-5 Hz rhythmic discharge of spike-and-wave complexes, and the behavioral arrests afflicting children with absence epilepsy. To test this hypothesis, the candidate will recreate the disease in mice using an epitope-tagged CACNA1H transgene that encodes Cav3.2. Nucleotide mutations will be made to recreate the epilepsy-associated amino acid changes F161L and V831M, which alter Cav3.2 channel gating. Second, he will target the gene to specific neuron subtypes by adding a Cre recombinase delete-able trancriptional and translational silencing element to the transgene. Because they contain cell-type specific promoters, the Cre transgenes express Cre recombinase protein in limited neuron subtypes. Only in these neurons will Cre delete the silencing element, cause transgene expression, and generate epitope tag staining. In this study, the candidate will test whether abnormal burst firing in cortical pyramidal or reticular thalamic neurons cause absence epilepsy. If the characteristic signs of epilepsy are reproduced, it will establish that mutations in Cav3.2 cause absence epilepsy. Targeted expression of this mutant gene will identify the responsible neurons. Identifying the neural substrate will facilitate work to identify other disease genes and potential drug targets. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02NS054674-02
Application #
7227768
Study Section
NST-2 Subcommittee (NST)
Program Officer
Stewart, Randall R
Project Start
2006-05-01
Project End
2011-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$169,576
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Kasten, Michael R; Anderson, Matthew P (2015) Self-regulation of adult thalamocortical neurons. J Neurophysiol 114:323-31
Krishnan, Vaishnav; Tarula, Erick; Anderson, Matthew P et al. (2013) Postictal bradyarrhythmia following an isolated seizure in a patient with left hemisphere stroke. Seizure 22:908-10
Zhou, Yu-Dong; Zhang, Dawei; Ozkaynak, Ekim et al. (2012) Epilepsy gene LGI1 regulates postnatal developmental remodeling of retinogeniculate synapses. J Neurosci 32:903-10
Smith, Stephen E P; Elliott, Robin M; Anderson, Matthew P (2012) Maternal immune activation increases neonatal mouse cortex thickness and cell density. J Neuroimmune Pharmacol 7:529-32
Smith, Stephen E P; Xu, Lin; Kasten, Michael R et al. (2012) Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels. J Neurochem 120:611-21
Czupryn, Artur; Zhou, Yu-Dong; Chen, Xi et al. (2011) Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice. Science 334:1133-7
Smith, Stephen E P; Zhou, Yu-Dong; Zhang, Guangping et al. (2011) Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med 3:103ra97
Anderson, Matthew P (2010) Arrested glutamatergic synapse development in human partial epilepsy. Epilepsy Curr 10:153-8
Zhou, Yu-Dong; Lee, Sanghoon; Jin, Zhe et al. (2009) Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat Med 15:1208-14
Wüthrich, Christian; Dang, Xin; Westmoreland, Susan et al. (2009) Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons. Ann Neurol 65:742-8

Showing the most recent 10 out of 11 publications