The Laboratory of Epilepsy and Neurodevelopment

Focal cortical dysplasia (FCD) is the most common underlying pathology in children with drug-resistant epilepsies. Using the combination of molecular genetics, electrophysiology and human clinical data, we aim to focus on defining the underlying genetic, cellular, and circuits mechanisms contributing to focal cortical epilepsies as well as establishing the critical roles of specific genes in cortical development.

Glioblastoma multiforme (GBM) is the most horrifying neurological disease. The majority patients die within 15 months of their diagnosis. We used CRISPR/CAS9 technology to introduce LoF mutations specifically in postnatal subventricular progenitors and created an animal mode that recapitulates the features of human GBM at genetic, imaging and clinical levels, paving ways to therapeutic development.

A novel therapeutic target in mTOR pathway has been identified. Conditional expressing vectors have been developed to test whether and how this small molecule prolongs the survival time of GBM animals or suppress seizures in FCD animals with hope to translate this novel and exciting new target into clinical application.

Selected publications

  • Manent JB, Wang Y, Chang Y, Paramasivam M, LoTurco JJ: Dcx reexpression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder. Nat Med 15(1):84-90, 2009. PM19098909/PMC2715867

  • Wang Y, Yin X, Rosen G, Gabel L, Guadiana SM, Sarkisian MR, Galaburda AM, Loturco JJ: Dcdc2 knockout mice display exacerbated developmental disruptions following knockdown of doublecortin. Neuroscience 190: 398-408, 2011. PM21689730/PMC3170724

  • Wang Y, Ji T, Nelson AD, Glanowska K, Murphy GG, Jenkins PM, Parent JM: Critical roles of αII spectrin in brain development and epileptic encephalopathy. J Clin Invest 128(2): 760-773, 2018. PM29337302/PMC5785268

  • Hu S, Knowlton RC, Watson BO, Glanowska KM, Murphy GG, Parent JM, Wang Y: Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA. Ann Neurol 84(1): 140-146, 2018. PM30080265/PMC6119494

  • Hu S, Yang T, Wang Y: Widespread labeling and genomic editing of the fetal central nervous system by in utero CRISPR AAV9-PHP.eB administration. Development 148(2): 2021. PM33334860/PMC7847274

  • Kao HY, Hu S, Mihaylova T, Ziobro J, Ahn E, Fine C, Brang D, Watson BO, Wang Y: Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model. Epilepsia 62(5): 1268-1279, 2021. PM33735460/PMC8211029

  • Hu S, Kao HY, Yang T, Wang Y: Early and Bi-hemispheric seizure onset in a rat glioblastoma Multiforme model. Neurosci Lett 766: 136351, 2022. PM34793898/PMC8642883

  • Yang T, Hu ST, Chang WC, Kao HY, Wang Y: Perineuronal nets degradation and parvalbumin interneuron loss in a mouse model of DEPDC5-related epilepsy. Dev Neurosci, 2022 (accepted with minor revision).

  • Kao HY, Hu ST, Yang T, Wang Y: Depdc5 deletion in forebrain excitatory neurons is sufficient to cause seizure and SUDEP. Exp Neurol, 2022 (submitted).

ACTIVE EXTRAMURAL SUPPORT

U54NS117170 (Project 3 lead) NIH (NINDS) 2020-2025

Epilepsy Multiplatform Variant Prediction (EpiMVP): Project 3: Cell Systems to Pre-Clinical Models

R01 NS113824 (Wang) NIH (NINDS) 9/2019~9/2024

Cortical development and pathogenesis in DEPDC5-related epilepsies