טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentLaifenfeld Daphna
SubjectRegulatory Effects of Norepinephrine on Genes Involved in
Cell Survival and Synaptic Connectivity:
Implications to Major Depression
DepartmentDepartment of Medicine
Supervisors Professor Dorit Ben-Shachar
Professor Emeritus Ehud Klein


Abstract

 Recently major depression has been considered a disorder of neuronal plasticity, likely governed by corresponding alterations in the expression of plasticity genes. The present work was aimed at assesing whether norepinephrine (NE), an immediate target of antidepressants, could initiate events of neuronal plasticity, and whether these could be involved in the etiology and treatment of major depression. NE treatment (10-5M/48h) resulted in increased neuronal differentiation in SH-SY5Y neuroblastoma cells, along with an increase in the cell-adhesion molecule L1 (CAM-L1), in laminin, and in the transcription factor cAMP response element binding protein (CREB), all involved in processes of cell survival and neurite outgrowth. Next, we examined whether CAM-L1, laminin, and CREB are altered in animal models relevant to the etiology and treatment of depression. Antidepressants induced increases in mRNA and protein levels of CAM-L1, laminin, and pCREB, in a brain region specific manner in chronically treated rats. In rats four months after the termination of prolonged stress exposure a decrease in mRNA and protein levels of CAM-L1, laminin and pCREB was observed. Finally, the expression of CAM-L1, laminin, and CREB was examined in 59 post-mortem specimens of psychiatric patients obtained from the Stanley Foundation Brain Collection, from the ventral parieto-occipital cortex, and the prefrontal cortex.. Alterations were observed in CAM-L1 specifically in the depressed group in both brain regions, along with less specific alterations in laminin and pCREB. Moreover, medicated depressed patients differed from unmedicated patients in the expression of CAM-L1, laminin, and pCREB. Taken together these results strongly implicate CAM-L1 in the pathophysiology and treatment of depression.