Photo Credit: Kaisha Meyer

iPSC Models & Genetic Epilepsies

Genetic epilepsies in pediatric patients pose specific difficulties in diagnosis and treatment as they are typically refractory to conventional therapies, associated with poor developmental outcomes, and co-morbid with cerebral palsy, autism, and other neuropsychiatric conditions. Single gene epilepsy syndromes, so-called developmental and epileptic encephalopathies, provide a window to study these diseases using patient specific models.

In collaboration with the UTSA Stem Cell Core, we are making patient-derived induced pluripotent stem cells to study monogenic epilepsies. We are employing several novel cell culture innovations, including 3D neuronal cultures called “brain organoids”. Use of CRISPR/Cas9 gene-editing technology allows for creation of isogenic controls facilitating analysis of molecular phenotypes attributable to the specific genetic mutation. We hope to translate our findings to educate treatment of these challenging diseases.

Adult Neurogenesis & Epilepsy

Adult mammalian neural stem cells in the hippocampal dentate gyrus are a subject of intense study based on their biological properties and potential medical significance. Neural stem cells can self-renew and differentiate into neurons and glial cells (astrocytes and oligodendrocytes) during development and in the adult central nervous system. After a severe brain insult, neural stem cells proliferate and migrate aberrantly and contribute to epilepsy progression.

We are interested in the identification of the molecular, cellular and circuit-based mechanisms regulating self-renewal and fate specification of adult neural stem cells and plasticity of newborn neurons in both physiological and pathological contexts, such as epilepsy. Our laboratory is using an integrated approach to investigate rodent and human neural stem cells both in vitro and in animal models utilizing techniques in single cell biology, virology, mouse genetics, electrophysiology, optogenetic/DREADD manipulation, Ca2+ imaging, and video/EEG recording.

Photo Credit: Gopakumar Changarathil
Photo Credit: Zacharie Maloney

Human 3D Brain Organoid Models of Neurological Disorders

Recent advances in stem cell technology and the ability to generate 3D brain organoids that resemble specific regions of the brain including cortex, hippocampus, midbrain, and striatum has opened new avenues to model neurodevelopmental and neurodegenerative disorders. Using these systems, we have begun to decipher the role of genes in normal and abnormal brain development, with the ultimate goal of using these models to develop precision brain therapeutics to treat these conditions.

Hsieh Lab Graphical Abstract

Graphical summary of Hsieh lab approaches, models and tools

Photo Credit: Kaisha Meyer, Courtney McMahon