Norepinephrine alters the expression of genes involved in neuronal sprouting and differentiation: relevance for major depression and antidepressant mechanisms.
Recent research into depression has focused on the involvement of long-term intracellular processes, leading to abnormal neuronal plasticity in brains of depressed patients, and reversed by antidepressant treatment. Given a suggested decrease in noradrenergic transmission in depression, and an antidepressant induced increase in norepinephrine (NE) level, a possible role for NE in mediating alterations in neuronal morphology and plasticity was examined. Human neuroblastoma SH-SY5Y cells treated with 10-5 m NE presented an elongated granule-rich cell-body and increased number of neurites, when compared with non-treated cells. Moreover, cell survival was enhanced in the presence of NE, while proliferation was inhibited. The above effects suggest a role for NE in cell differentiation. Indeed similar effects on cell survival and neurite outgrowth were induced in SH-SY5Y cells by retinoic acid (RA), an established differentiating agent. Finally, NE treatment resulted in a progressive decrease in the pluripotent marker Oct4 and an increase in the neuronal growth cone marker, growth-associated-protein 43 (GAP-43). Alongside these effects, NE-treated cells presented alterations in the expression of 44 genes as observed in a neurobiology cDNA microarray. Among the altered genes, an increase in the expression level of two neurite-outgrowth promoting genes, neural cell adhesion molecule L1 and laminin, was confirmed by RT-PCR. Taken together, the results support a role for NE in processes of synaptic connectivity, and may point to a role for this neurotransmitter in mediating the suggested neuronal plasticity in depression and in antidepressant treatment.
Laifenfeld
Daphna
D
Laboratory of Psychobiology, The Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel.
Klein
Ehud
E
Ben-Shachar
Dorit
D
D015102:3,4-Dihydroxyphenylacetic Acid / Q000493:pharmacokinetics; D000943:Antigens, Differentiation / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003865:Major Depressive Disorder / Q000209:etiology / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009638:Norepinephrine / Q000493:pharmacokinetics / Q000494:pharmacology*; D050814:Octamer Transcription Factor-3; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D019922:GAP-43 Protein; D007797:Laminin; D039842:Neural Cell Adhesion Molecule L1; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D014157:Transcription Factors; D015102:3,4-Dihydroxyphenylacetic Acid; D014212:Tretinoin; D009638:Norepinephrine