Dorit Ben-Shachar, PhD
Associate Professor of Neuroscience and Psychobiology
PhD, 1985 - Technion, Israel
Multifaceted dysfunction of mitochondria in schizophrenia
Schizophrenia, which afflicts about 1% of the population worldwide, is currently regarded as a neurodevelopmental disorder with impaired neuronal connectivity and synaptic plasticity. Our hypothesis is that abnormal energy production in neurons can lead to such impairments. Mitochondria are key players in energy production and are therefore the focus of our research. We study the functional and molecular properties of the first complex (CoI) of the respiratory chain, including its activity, expression of subunits, their transport into the mitochondria and assembly into the holocomplex. The role of mitochondria in neuronal differentiation is also investigated, using schizophrenia-derived iPSC and developmental animal models of schizophrenia. Our goal is to delineate the link between mitochondrial dysfunction and the impaired neuronal differentiation in schizophrenia. In addition, we study the effects of psychotropic treatments on various mitochondrial parameters in an attempt to produce a mitochondrial profile for personalized medicine.
Asor E, Belhanes H, Kavushansky A, Zubedat S, Klein E, Avital A, and Ben-Shachar D. 2014. Transient early interference with the expression of multiple genes leads to disparate behavioral response to sub-chronic and chronic stress in rats. Psychoneuroendocrinol. 38, 2173-2183.
Kavushansky A, Kritman M, Maroun M, Klein E, Richter-Levin G, Hui KS, and Ben-Shachar D. 2013. Opioid-degrading enzymes in individual reactivity to traumatic stress. Eur Neuropsychopharmacol. 23, 1179-1788.
Robicsek O, Karry R, Petit I, Salman-Kesner N, Müller FJ, Klein E, Aberdam D, and Ben-Shachar D. 2013. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol. Psychiatry. 18, 1067-76.
Petit I, Salman N, Robicsek O, Karry R, Aberdam D, and Ben-Shachar D. 2012. Induced Pluripotent Stem Cells derived from human hair follicles as a cellular model for neurodevelopmental disorders. Stem Cell Res. 8, 134-140.
Rosenfeld M, Brenner-Lavie H, Gal-Ben AS, Kavushansky K, and Ben-Shachar D. 2011. Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia. Biol. Psychiatr. 69, 980-988.
Mitochondria exhibit multifaceted and disease specific dysfunction in schizophrenia.
Impaired functioning of complex I (CoI) of the electron transfer chain together with changes in the expression of its subunits and their assembly into the holocomplex are observed (A). Cellular respiration (B), mitochondrial membrane potential (ΔΨm) and network dynamics (C) are abnormal in schizophrenia. A pathological interaction is observed between mitochondria (specifically CoI) and dopamine, a hallmark of the disease. Mitochondrial abnormalities are linked to impaired differentiation of schizophrenia-derived iPSC into neurons (D). Transfer of healthy mitochondria into differentiating iPSC results in improved mitochondrial function and partially rescues neuronal differentiation (E). Studies are conducted using blood cells, hair follicle-derived iPSC and brain specimens derived from patients with schizophrenia.