OLEKSANDR (ALEX) SHCHEGLOVITOV
The Shcheglovitov Lab
Assistant Professor of Neurobiology and Anatomy
Neurobiology of Disease
Development and function of human synapses in health and disease
Synapses provide the major biochemical substrates for the development and execution of cognitive functions in the brain. Correspondingly, mutations in synaptic proteins have been identified in patients with various mental illnesses. Due to the very limited access to the human brain, mechanisms of synaptic development and function have been mainly investigated in animal models. However, major differences between animals and humans make it difficult to translate the results acquired in animals into treatments for patients. As a result, medicines that are currently available for patients with autism, intellectual disability, bipolar disorders, depression, schizophrenia, and other neuropsychiatric disorders are largely unspecific with serious side effects. Therefore, there is a critical need to study synapses in human neurons. We study the development and function of human synapses under normal and pathological conditions using human neurons derived from induced pluripotent stem cells (iPSCs).
We start with skin cells of patients with different neuropsychiatric disorders that carry specific genetic abnormalities in genes encoding synaptic proteins. We reprogram skin cells into iPSCs and differentiate iPSCs into neurons. We study synaptic properties of human neurons using electrophysiology, imaging, biochemistry, and molecular biology techniques. We seek to understand the molecular mechanisms underlying the development and function of human synapses under normal and pathological conditions.
*Eckle, V.S., *Shcheglovitov, A., *Vitko, I., Dey, D., Yap, C.C., Winckler, B., and Perez-Reyes, E. (2014) Mechanisms by which CACNA1H mutations found in epilepsy patients increase seizure susceptibility. Journal of Physiology, 592(Pt 4):795-809. (*equally contributed authors)
Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., Krawisz, A., Froehlich, W., Bernstein, J.A., Hallmayer, J., and Dolmetsch, R.E. (2013) Shank3 and IGF1 Restore Synaptic Deficits in Neurons from 22q13 Deletion Syndrome Patients. Nature, 503(7475):267-271.
Featured in: Cell (Dec 13, 2013); Faculty of 1000
Krey, J.F., Paşca, S.P., Shcheglovitov, A., Yazawa, M., Schwemberger, R., Rasmusson, R., and Dolmetsch, R.E. (2012) Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nature Neuroscience, 16(2):201-209.
*Shcheglovitov, A., Vitko, I., Lazarenko, R., Orestes, P., Todorovic, S.M., and *Perez-Reyes, E. (2012) Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Cav2.3 calcium channels. Journal of General Physiology, 139(3):219-234. (*corresponding authors)
Paşca, S.P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Paşca, A.M., Cord, B., Palmer, T.D., Chikahisa, S., Seiji, N., Bernstein, J.A., Hallmayer, J., Geschwind, D.H., and Dolmetsch, R.E. (2011) Using iPS cell-derived neurons to uncover cellular phenotypes in patients with Timothy Syndrome. Nature Medicine, 17(12):1657-1662.
Featured in: Nat Med (Dec 6, 2011); Nat Rev Neurosci (Dec 20, 2011); Faculty of 1000
*Yoo, A.S., *Sun, A.X., *Li, L., *Shcheglovitov, A., Portmann, T., Li, Y., Lee-Messer, C., Dolmetsch, R.E., Tsien, R.W., and Crabtree, G.R. (2011) MicroRNA-Mediated Conversion of Human Fibroblasts to Neurons. Nature, 476(7359):228-231. (*equally contributed authors)
Featured in: Nature 476 (7359); Faculty of 1000
Nguyen, H.N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P., Kee, K., Schüle, B., Dolmetsch, R.E., Langston, W., Palmer, T.D., and Reijo-Pera, R. (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell, 8(3):267-280.
Park, C.Y., Shcheglovitov, A., and Dolmetsch, R. (2010) The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels. Science, 330(6000):101-105.
Featured in: Science 330(6000); Faculty of 1000;
Google Scholar: http://scholar.google.com/citations?user=99Y5cegAAAAJ&hl=en