Translational regulation in the adult brain: mediated by BDNF signalling, stress, and chronic antidepressant treatment
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One of the most amazing features of the brain is its plasticity. This is a fundamental process by which the brain acquires information and makes the appropriate adaptive changes, a process that makes us able to think, feel, and remember. Synaptic plasticity refers to the ability of connections between neurons, the synapses, to change in strength following activity. Dysfunctional synaptic plasticity is recognized as a key factor in several neurological and psychiatric disorders, including major depressive disorder. The consolidation of long-term changes in synaptic connectivity typically requires gene expression and protein synthesis. Recent work shows that post-transcriptional regulation of mRNA translation is critical for consolidation of synaptic plasticity and long-term memory. The secretory peptide, brainderived neurotrophic factor (BDNF) has been identified as a possible common mediator of translational regulation and synaptic plasticity. However, the role of post-transcriptional mechanisms in stress and depression are little understood. This thesis examines post-transcriptional regulation by BDNF during synaptic plasticity, and how translation is regulated in response to antidepressant treatment and stress. First we examined the effects of BDNF on translational regulation when BDNF was infused into the dentate gyrus in vivo, and following directly application to isolated synapses in vitro (synaptodendrosomes). The results indicate a compartment-specific regulation of translation in the dentate gyrus in response to BDNF. In synaptodendrosomes, BDNF rapidly enhances phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and enhances synaptic protein expression. In vivo, local infusion of BDNF induces long-term potentiation (BDNFLTP) of synaptic transmission at perforant path granule cell synapses, associated with phosphorylation of eIF4E and eukaryotic elongation factor 2 (eEF2). BDNF-LTP and changes in translation factor phosphorylation state are dependent on activation of the extracellular signal-regulated kinase (ERK). Next, we examined the effect of systemic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. We show that chronic, but not acute, injections with fluoxetine induces region-specific effects on translation factor activity. Interestingly, chronic fluoxetine, like BDNF-infusion, increased phosphorylation of eIF4E and eEF2 specifically in the dentate gyrus. The RNA-binding protein cytoplasmic polyadenylation element-binding protein (CPEB), which regulates translation of specific mRNAs, was hyperphosphorylated in the prefrontal cortex and hippocampus proper following chronic fluoxetine treatment. This effect was sustained in the hippocampus proper up to one week after cessation of treatment. In addition, chronic fluoxetine induced brain region-specific expression of two atypical CPEB isoforms, CPEB3 and CPEB4. Together, these findings support a role for post-transcriptional regulation in the delayed action of antidepressant drugs. Finally, we examined the effect of chronic mild stress (CMS) as well as acute sleep deprivation, a potential antidepressant treatment in humans, on post-transcriptional mechanisms of gene expression in the prefrontal cortex, hippocampus proper and dentate gyrus. Groups of rats received either: 1) ordinary daily care, 2) 4 weeks of chronic mild stress, 3) a single 8 hour session of total sleep deprivation, or 4) four weeks of CMS followed by sleep deprivation. The results demonstrate region-specific post-transcriptional regulation in response to CMS and sleep deprivation. In the dentate gyrus and hippocampus proper, eIF4E and eEF2 phosphorylation were selectively modulated by SD, indicating a suppression of general protein synthesis in these structures. In the prefrontal cortex, phosphorylation of eIF4E is enhanced following both CMS and sleep deprivation, indicating enhancement of translational initiation and protein synthesis. These regional differences were further supported by differential regulation of genes (Arc and BDNF) previously coupled to synaptic plasticity and antidepressant responses. We conclude that post-transcriptional regulation is affected not only during BDNFLTP, but also in a brain region-specific manner following stress and antidepressant treatment.
Paper I: Journal of Neurochemistry 99(5), Kanhema, T.; Dagestad, G.; Panja, D.; Tiron, A.; Messaoudi, E.; Håvik, B.; Ying, S. W.; Nairn, A. C.; Sonenberg, N.; Bramham, C. R., Dual regulation of translation initiation and peptide chain elongation during BDNF-induced LTP in vivo: evidence for compartment-specific translation control, pp. 1328–1337. Copyright 2006 The Authors, Journal Compilation 2006 International Society for Neurochemistry. Published by Blackwell. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1111/j.1471-4159.2006.04158.xPaper II: European Journal of Neuroscience 23(10), Dagestad, G.; Kuipers, S. D.; Messaoudi, E.; Bramham, C. R., Chronic fluoxetine induces region-specific changes in translation factor eIF4E and eEF2 activity in the rat brain, pp. 2814–2818. Copyright 2006 The Authors, Journal Compilation Federation of European Neuroscience Societies and Blackwell Publishing. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1111/j.1460-9568.2006.04817.xPaper III: Dagestad, G.; Bramham, C. R., 2010, Chronic fluoxetine induces phosphorylation of CPEB1 and brain region-specific expression of CPEB3 and CPEB4. Full text is not available in BORA.Paper IV: Dagestad, G.; Grønli, J.; Milde, A. M.; Murison, R.; Portas, C. M.; Bramham, C. R., 2010, Sleep deprivation and chronic mild stress acts at the posttranscriptional level: brain region-specific regulation of translation factor activity and CPEB phosphorylation. Full text not available in BORA.