Professor - Department of Neurology Professor - Department of Neuroscience Professor - Department of Molecular and Human Genetics Director - Blue Bird Circle Developmental Neurogenetics Laboratory Ph.D., Stanford University, 1977 M.D., Yale University, 1981 One Baylor Plaza Baylor College of Medicine Houston TX, 77030 Telephone: 713-798-5860 - Fax: 713-798-7528 Email: jnoebels@bcm.edu

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 also explore the presynaptic release process and activity-induced changes of downstream gene expression in epileptic brain to identify regulatory pathways that are critical mechanisms of disease progression.

At present, mutant mouse models of inherited disorders in neuronal excitability are under investigation using in vitro cell physiology and optical fluorescence measurements of ion channel activity and exocytosis in presynaptic terminals of mouse brain slices, as well as molecular anatomical techniques including laser-capture microspcopy and realtime quantitative PCR, in situ hybridization and immunohistochemistry, and microarray analysis of seizure-activated mRNAs. 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. The Human Channelopathy Project will evaluate the contribution of SNP profiles in several hundred ion channel subunit genes to the complex inheritance of neurological excitability disorders such as epilepsy.

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Glasscock, E, Qian J, Yoo, J, Noebels, JL.  Masking Epilepsy by Combining Two Epilepsy Genes. Nat. Neuroscience, 2007 10:1554-8.

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  Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron, 2007 55:697-711.

Qian J, Noebels JL. Exocytosis of vesicular zinc reveals persistent depression of neurotransmitter release during metabotropic glutamate receptor long-term depression at the hippocampal CA3-CA1 synapse. J Neurosci. 2006  26:6089-95.

Brenner R, Chen QH, Vilaythong A, Toney GM, Noebels JL, Aldrich RW (2005). Deletion of BK channel b 4 subunit increases dentate granule cell excitability and causes non-convulsive temporal lobe seizures. Nat. Neurosci., 2005 8:1752-9.

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.

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.

Senechal KR, Thaller C, Noebels JL (2005). ADPEAF Mutations Reduce Levels of Secreted LGI1, a Putative Tumor Suppressor Protein Linked to Epilepsy. Hum. Mol. Genet. 14: 1613-1620.

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.

Zhang Y, Vilaythong A, Yoshor D, Noebels JL (2004). Elevated thalamic low voltage activated currents precede the onset of absence epilepsy in the SNAP25 deficient mouse mutant Coloboma. J. Neurosci. 24: 5239-5248.

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

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• Pedro Olivetti (Neuroscience)
• Jerrah Holth (Molecular and Human Genetics)

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Inherited calcium channel subunit mutations lead to spike-wave absence seizures.

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