ד"ר מורן רובינשטיין חייטין

מכון עינים ע"ש גולדשלגר סגל אקדמי בכיר
ד"ר מורן רובינשטיין חייטין

מחקר

בשנים האחרונות היתה פריצת דרך  בזיהוי הגורמים הגנטים למחלות מוחיות, אבל ברובן, עדיין לא ברור למה המוטציה גורמת למחלה. .  על מנת לגשר על הפער הזה אנו משלבים שיטות מחקר מגוונות המתחקות אחר השינויים מרמת הנוירון הבודד, רשת הנוירונים והחיה השלמה. 

באופן ספציפי אנחנו חוקרים את הבסיס העצבי לאפילפסית ילדים קשה, סנדרום דרווט (Dravet Syndrome). מחלה זו נגרמת בגלל מוטציה בתעלות נתרן תליות מתח וגורמת בחולים לפרכוסים חוזרים וקשים שאינם מגיבים לתרפות, לאוטיזם, פיגור והפרעות התנהגות נוספות. 

Research

The Molecular Basis of Epileptic Encephalopathies and Autism

We study the neuronal and molecular basis of visual system abnormalities in severe epilepsy and autism. One out of every 68 children is diagnosed with an autism spectrum disorder, characterized by impaired social skills. Moreover, autistic features are observed in people suffering from epileptic encephalopathies, a group of severe disorders characterized by refractory seizures and cognitive deficit with limited treatment options and poor prognosis.

 

Visual system abnormalities are often observed in both disorders, ranging from lack of eye contact, through abnormal visual processing, to photosensitive seizures. The tremendous advancement in genetic studies helped to identify the involvement of many genes in the etiology of epilepsy and autism. However, our understanding of the pathways leading from a genetic mutation to abnormal brain function is still in its infancy. Ion channels are molecular machines, crucial for transforming synaptic inputs into electrical response, controlling neuronal firing and neurotransmitter release. One of the pivotal families of ion channels are the voltage-gated sodium channels (NaV). Indeed, mutations in multiple types of NaV channels were identified in epilepsy and autism patients. However, connecting the dots between NaV dysfunction and the resulting diseases have proven to be a formidable task.

 

In order to bridge this gap we harness the strength of mouse genetics, combined with electrophysiological recordings, to elucidate the molecular and neuronal basis of epilepsy and autism and to understand how genetic mutations in ion channels leads to these disorders. We use mouse models mimicking the human genetic mutation and unveil perturbations of neuronal function on cellular, network and behaving animal levels. Moreover, the contribution of different classes of neurons and different brain regions is tested using global and viral mediated localized selective genetic deletions. Finally, behavioral experiments are used to examine epilepsy, sociability and the function of the visual system.

 

From sodium channels dysfunction to epilepsy and autism

Tremendous advancement in genetic studies helped to identify the involvement of many genes in the etiology of epilepsy and autism. However, our understanding of the pathways leading from a genetic mutation to abnormal brain function is still in its infancy.
Ion channels mediate neuronal communication and firing. One of the pivotal families of ion channels are the voltage-gated sodium channels (Nav). Mutations in Nav were identified in epilepsy and autism patients, however, connecting the dots between Nav dysfunction and the resulting diseases have proven to be a formidable task. In order to bridge this gap we use mouse models mimicking the human genetic mutation and unveil perturbations of neuronal function on cellular, network and behaving animal levels. 
 
Dravet syndrome is an intractable childhood-onset epilepsy caused by loss of function mutations in Nav1.1. Dravet syndrome symptoms begin during the first year of life, with seizures often associated with fever, and progress to refractory and frequent seizures. Additionally Dravet patients develop cognitive deficit, autistic-like behaviours, hyperactivity and premature death. 

Using Dravet syndrome mouse model we:

Understand the relationship between seizures and cognitive impairment in Dravet Syndrome.

Explore functional interactions between different voltage gated sodium channels and compensatory mechanisms in Dravet Syndrome.

פרסים ומלגות

  1. Rubinstein, M., Patowary, A., Stanaway, I.B., McCord, E., Scheuer, T., Nickerson, D., Raskind, W.H., Wijsman, E.M., Bernier, R., Catterall, W.A. and Brkanac, Z. (Epub). Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Molecular Psychiatry.
  2. Yakubovich, D., Berlin, S., Kahanovitch, U., Rubinstein, M., Farhy-Tselnicker, I., Styr, B., Keren-Raifman, T., Dessauer, C.W., and Dascal, N. (2015). A quantitative model of the GIRK1/2 channel reveals that its basal and evoked activities are controlled by unequal stoichiometry of Gα and Gβγ. PLoS computational biology 11, e1004598.
  3. Rubinstein, M., Han, S., Tai, C., Westenbroek, R.E., Hunker, A., Scheuer, T., and Catterall, W.A. (2015). Dissecting the phenotypes of Dravet syndrome by gene deletion. Brain 138, 2219-2233.
  4. Rubinstein, M., Westenbroek, R.E., Yu, F.H., Jones, C.J., Scheuer, T., and Catterall, W.A. (2015). Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome. Neurobiology of disease 73, 106-117.
  5. Baek, J.H., Rubinstein, M., Scheuer, T., and Trimmer, J.S. (2014). Reciprocal changes in phosphorylation and methylation of mammalian brain sodium channels in response to seizures. The Journal of biological chemistry 289, 15363-15373.
  6. Kahanovitch, U., Tsemakhovich, V., Berlin, S., Rubinstein, M., Styr, B., Castel, R., Peleg, S., Tabak, G., Dessauer, C.W., Ivanina, T., and Dascal, N. (2014). Recruitment of Gbetagamma controls the basal activity of G-protein coupled inwardly rectifying potassium (GIRK) channels: crucial role of distal C terminus of GIRK1. The Journal of physiology.
  7. Berlin, S., Keren-Raifman, T., Castel, R., Rubinstein, M., Dessauer, C.W., Ivanina, T., and Dascal, N. (2010). G alpha(i) and G betagamma jointly regulate the conformations of a G betagamma effector, the neuronal G protein-activated K+ channel (GIRK). The Journal of biological chemistry 285, 6179-6185.
  8. Rubinstein, M., Peleg, S., Berlin, S., Brass, D., Keren-Raifman, T., Dessauer, C.W., Ivanina, T., and Dascal, N. (2009). Divergent regulation of GIRK1 and GIRK2 subunits of the neuronal G protein gated K+ channel by GalphaiGDP and Gbetagamma. The Journal of physiology 587, 3473-3491.
  9. Rubinstein, M., Peleg, S., Berlin, S., Brass, D., and Dascal, N. (2007). Galphai3 primes the G protein-activated K+ channels for activation by coexpressed Gbetagamma in intact Xenopus oocytes. The Journal of physiology 581, 17-32.
  10. Werner, H., Idelman, G., Rubinstein, M., Pattee, P., Nagalla, S.R., and Roberts, C.T., Jr. (2007). A novel EWS-WT1 gene fusion product in desmoplastic small round cell tumor is a potent transactivator of the insulin-like growth factor-I receptor (IGF-IR) gene. Cancer letters 247, 84-90.
  11. Rubinstein, M., Idelman, G., Plymate, S.R., Narla, G., Friedman, S.L., and Werner, H. (2004). Transcriptional activation of the insulin-like growth factor I receptor gene by the Kruppel-like factor 6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53. Endocrinology 145, 3769-3777.
אוניברסיטת תל-אביב, רחוב חיים לבנון 30, 6997801.
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