- Department of Neurology (Office)
- Baylor College of Medicine Medical Center McNair Campus 7200 Cambridge St., 9th Floor, MS: NB302 Houston, Texas 77030 United States
- Cullen Trust for Health Care Endowed Chair in Neurogenetics
- Professor Neurology, Neuroscience, and Molecular & Human Genetics
- Blue Bird Circle Developmental Neurogenetics Laboratory
- Baylor College of Medicine
- Vice Chair for Research
- Baylor College of Medicine
- Graduate Program Faculty
- Integrative Molecular and Biomedical Sciences;
- Translational Biology and Molecular Medicine
- Baylor College of Medicine
- Post-Doctoral Fellowship at Harvard University
- Residency at Massachusetts General Hospital
- PhD from Stanford University
- MD from Yale University School Of Medicine
- BA from Reed College
- American Board of Psychiatry and Neurology
- Gene control of neuronal excitability within the developing mammalian CNS
- Inherited neurological diseases
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 (tottering, lethargic, ducky, and stargazer, slow wave, and mocha) and are linked to mutations of voltage-gated calcium ion channels, AMPA receptor trafficking TARP subunits, a sodium hydrogen exchanger, and vesicular zinc trafficking. Study of these mice have led to the identification of novel members of the TARP 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, synaptic vesicle proteins, and transcription factors for interneuron migration 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 and conditional gene silencing 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.
Our laboratory recently discovered that mouse models of Alzheimer’s Disease show non-convulsive cortical hyperexcitability, heralding a paradigm change in understanding the basis for cognitive disorders in familial AD. We have also identified MAPT1, the gene for tau protein, as a critical modifier of AD-linked cognitive decline and epilepsy. Other models of Long QT interval genes link arrhythmias of heart and brain, and sudden unexpected 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, quantitative analysis of seizure-activated mRNAs, in vivo and in vitro cell physiology, 2 photon imaging, 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 and a $4.5 million NIH grant, our laboratory performed the first large-scale translational genomic research study examining variants in human ion channel genes. The Human Channelopathy Project revealed extensive complexity of disease-linked genes, and we are currently evaluating the contribution of SNP patterns and copy number variation in several hundred ion channel subunit genes to the complex inheritance of neurological excitability disorders such as epilepsy. A second and related large collaborative NIH funded Center project focusing on risk prediction of variants in ion channel genes linked to neurocardiac phenotypes is underway.
- Tang M, Gao G, Rueda CB, Yu H, Thibodeaux DN, Awano T, Engelstad KM, Sanchez-Quintero MJ, Yang H, Li F, Li H, Su Q, Shetler KE, Jones L, Seo R, McConathy J, Hillman EM, Noebels JL, De Vivo DC, Monani UR. "Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein." Nat Commun. 2017 January 20;8:14152. Pubmed PMID: 28106060
- Lopez AY, Wang X, Xu M, Maheshwari A, Curry D, Lam S, Adesina AM, Noebels JL, Sun QQ, Cooper EC. "Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder." Mol Psychiatry. 2016 Pubmed PMID: 27956739
- Aiba I, Wehrens XH, Noebels JL. "Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death." Proc Natl Acad Sci U S A. 2016;113(33):E4895-903. Pubmed PMID: 27482086
- Bomben VC, Aiba I, Qian J, Mark MD, Herlitze S, Noebels JL. "Isolated P/Q calcium channel deletion in layer VI corticothalamic neurons generates absence epilepsy." J Neurosci. 2016;36(2):405-18. Pubmed PMID: 26758833
- Noebels JL. "Single-gene determinants of epilepsy comorbidity." Cold Spring Harb Perspect Med. 2015 November 2;5(11) Pubmed PMID: 26525453
- Aiba I, Noebels JL. "Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models." Sci Transl Med. 2015;7(282):282ra46. Pubmed PMID: 25855492
- Kole MJ, Qian J, Waase MP, Klassen TL, Chen TT, Augustine GJ, Noebels JL. "Selective loss of presynaptic potassium channel clusters at the cerebellar basket cell terminal pinceau in Adam11 mutants reveals their role in ephaptic control of Purkinje cell firing." J Neurosci. 2015;35(32):11433-44. Pubmed PMID: 26269648
- Olivetti PR, Maheshwari A, Noebels JL. "Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome." Sci Transl Med. 2014;6(220):220ra12. Pubmed PMID: 24452264