Professor, Departments of Neurology, Neuroscience, and Molecular and Human Genetics; Program in Cell & Molecular Biology
Director, Blue Bird Circle Developmental Neurogenetics Laboratory

B.A., Reed College, 1972
Ph.D., Stanford University, 1977
M.D., Yale University, 1981
Postdoc, Harvard Medical School, 1983

RESEARCH INTERESTS:

The principal research strategy in the Developmental Neurogenetics Laboratory is to apply mutational analysis to learn how genes regulate neuronal excitability and network synchronization within the mammalian central nervous system. Spontaneous and transgenic mutations that express neurological phenotypes in the mouse provide a valuable opportunity to identify excitability genes and examine their role in synaptic plasticity in the developing brain.

Brain wave (EEG) phenotypes emerge from altered neuronal signaling properties, and are of special interest. Six mouse mutants causing spike-wave synchronization of the neocortex have been discovered in our laboratory, and four (tottering, lethargic, ducky, and stargazer) are linked to mutations of subunits of neuronal voltage-gated calcium ion channels. Study of these mice have led to the identification of novel members of the gene family, and a new understanding of how related molecules rescue function and determine selective vulnerability within thalamocortical pathways. Other new mouse models for human epilepsy syndromes involving mutant ion channel, receptor, and synaptic vesicle proteins are being analyzed to pinpoint the neural network and specific electrophysiological abnormalities characteristic of the human disorder. We are also exploring activity-induced changes of downstream gene expression in epileptic brain to identify regulatory pathways that are critical mechanisms of disease progression. Some of these genes, such as those for glutamate and GABA transporters and apoptotic pathways suggest distinct mechanisms for seizure-induced excitotoxicity and cell death.

At present, mutant mouse models of inherited disorders in neuronal excitability are under investigation using the molecular anatomical techniques of in situ hybridization and immunohistochemistry, differential display of seizure-activated mRNAs, in vitro cell physiology, and optical fluorescence measurements of ion channel activity in presynaptic terminals of mouse brain slices. These studies form the basis for development of strategies to selectively correct the tissue expression of neuronal gene errors early in development.

In collaboration with the Baylor Human Genome Sequencing Center, a large-scale translational genomic research study examining variants in human ion channel genes is currently in progress. This Human Channelopathy Project will evaluate the contribution of SNP patterns in several hundred ion channel subunit genes to the complex inheritance of neurological excitability disorders such as epilepsy.

SELECTED PUBLICATIONS:

1. Seal RP, Akil O, Yoo J, Weber C, Clause A, Kandler K, Noebels JL, Lustig LR, Edwards R (2008). Sensorineural Deafness and Seizures in Mice Lacking Vesicular Glutamate Transporter 3. Neuron 57: 263-275.

2. Glasscock E, Qian J, Yoo J, Noebels JL (2007). Masking Epilepsy by Combining Two Epilepsy Genes. Nat. Neurosci. 10: 1554-1558.

3. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Ly NB, Yoo J, Ho1 KO, Yu1 GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L (2008). Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55: 697-711.

4. Brenner R, Chen QH, Vilaythong A, Toney GM, Noebels JL, Aldrich RW (2005). BK channel b4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nat. Neurosci. 8: 1752-1759.

5. Cobos I, Calcagnotto ME, Vilaythong A, Noebels JL, Baraban SC, Rubenstein JLR (2005). Mice lacking the Dlx1 transcription factor exhibit subtype-specific loss of interneurons, reduced synaptic inhibition and epilepsy. Nat. Neurosci. 8: 1059-1068.

6. Qian J, Noebels JL (2005). Visualization of transmitter release with zinc fluorescence detection at the hippocampal mossy fiber synapse. J. Physiol. 566.3: 747-758.

7. Mori M, Burgess DL, Gefrides LA, Foreman PJ, Opferman JT, Korsmeyer SJ, Cavalheiro EA, Naffah-Mazzacoratti MG, Noebels JL (2004). Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons. Cell Death Differ. 11: 1223-1233.

8. Noebels JL (2003). The Biology of Epilepsy Genes. Ann. Rev. Neurosci. 26: 599-625.

9. Noebels JL (2001). The Inherited Epilepsies. In The Metabolic and Molecular Basis of Inherited Disease 8th edition. Scriver, Beaudet, Sly, Valle (eds.) McGraw Hill, New York, 5807-5832.

For more publications, see listing on Pub Med.

CONTACT INFORMATION:

Jeffrey L. Noebels, M.D., Ph.D.
Department of Neurology
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030, U.S.A.

Phone: 713-798-5860
Fax: 713-798-7528
E-mail:

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