Cellular Plasticity Cascades: Genes-To-Behavior Pathways in Animal Models of Bipolar Disorder
ABSTRACT Despite extensive research, the molecular/cellular underpinnings of bipolar disorder (BD) remain to be fully elucidated. Recent data has demonstrated that mood stabilizers exert major effects on signaling that regulate cellular plasticity; however, a direct extrapolation to mechanisms of disease demands proof that manipulation of candidate genes, proteins, or pathways result in relevant behavioral changes.
We critique and evaluate the behavioral changes induced by manipulation of cellular plasticity cascades implicated in BD.
Not surprisingly, the behavioral data suggest that several important signaling molecules might play important roles in mediating facets of the complex symptomatology of BD. Notably, the protein kinase C and extracellular signal-regulated kinase cascades might play important roles in the antimanic effects of mood stabilizers, whereas glycogen synthase kinase (GSK)-3 might mediate facets of lithium's antimanic/antidepressant actions. Glucocorticoid receptor (GR) modulation also seems to be capable to inducing affective-like changes observed in mood disorders. And Bcl-2, amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, and inositol homeostasis represent important pharmacological targets for mood stabilizers, but additional behavioral research is needed to more fully delineate their behavioral effects.
Behavioral data support the notion that regulation of cellular plasticity is involved in affective-like behavioral changes observed in BD. These findings are leading to the development of novel therapeutics for this devastating illness.
- SourceAvailable from: Nasser Haddjeri
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- "However, the development of novel antimanic agents and the understanding of the pathophysiology of this disease have been hampered by the lack of suitable animal models. Currently, there is still a need for animal models that reflect the oscillating nature of bipolar disorder ; the majority of current preclinical research utilizes separate models to measure facets of bipolar disorder, typically either mania or depression (Einat and Manji, 2006). Amphetamineinduced hyperactivity is the most widely used rodent animal model to test the efficacy of antimanic therapeutics (Young et al., 2011). "
ABSTRACT: Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania. Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control. We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD. Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties. © The Author 2015. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 10/2014; 18(2). DOI:10.1093/ijnp/pyu031 · 5.26 Impact Factor
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- "NTRK2 is an essential modulator of neural differentiation and cell survival and abundantly expressed in specific regions of human brain such as prefrontal cortex (Luberg et al. 2010). Recently, there is increasing evidence supporting that the impairment of neural plasticity is involved in the etiology and pharmacology of BD (Einat and Manji 2006; Zarate et al. 2006). More importantly, there are reports that the signal transduction BDNF/NTRK2 pathway might be involved in the pathogenesis of BP and the therapeutic mechanism of lithium in the treatment of BP (Hashimoto et al. 2004; Shaltiel et al. 2007). "
ABSTRACT: There is increasing evidence supporting the relationship between bipolar disorder (BP) and neurotrophin. The present study investigated the relationship between neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene polymorphisms and bipolar I disorder (BP I) susceptibility and treatment response to mood stabilizers (lithium or valproate). Two-hundred eighty-four patients who met the DSM-IV criteria for BP I and 295 matched healthy controls were enrolled into this study. TaqMan® SNP genotyping assays were applied to genotype three NTRK2 gene polymorphisms (rs2769605, rs1565445, rs1387923). Our study showed a significant allelic association between NTRK2 gene polymorphism rs2769605 and treatment response to mood stabilizers in BP I patients (t = -2.53, P = 0.01). However, no significant association between NTRK2 gene polymorphisms and BP I susceptibility was observed after correcting for multiple comparisons. The results suggest that the NTRK2 gene polymorphism likely plays an essential role in treatment response to mood stabilizers in Han Chinese BP I patients.Journal of Molecular Neuroscience 01/2013; DOI:10.1007/s12031-013-9956-0 · 2.76 Impact Factor
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- "Besides hyperactivity, bipolar patients in manic state often display poor judgment and increased impulsivity, leading to risk-taking behavior. We thus examined whether pharmacological manipulations of PKC could alter risk-taking behaviors, which can be assessed in rodents as a mirror image of anxiety-like behaviors in established tests for anxiety, such as the EPM and the OF tests (Einat and Manji, 2006). These tests are both based on the natural conflict between the drive to explore a new environment and the tendency to avoid a potentially dangerous area (Carobrez and Bertoglio, 2005; Prut and Belzung, 2003). "
ABSTRACT: The neurobiological mechanisms underlying the pathophysiology and therapeutics of bipolar disorder are still unknown. In recent years, protein kinase C (PKC) has emerged as a potential key player in mania. To further investigate the role of this signaling system in mood regulation, we examined the effects of PKC modulators in behavioral tests modeling several facets of bipolar disorder and in adult hippocampal cell proliferation in rats. Our results showed that a single injection of the PKC inhibitors tamoxifen (80 mg/kg, i.p.) or chelerythrine (3 mg/kg, s.c.) attenuated amphetamine-induced hyperlocomotion and decreased risk-taking behavior, supporting the efficacy of PKC blockade in acute mania. Moreover, chronic exposure to tamoxifen (10 mg/kg/day, i.p., for 14 days) or chelerythrine (0.3 mg/kg/day, s.c., for 14 days) caused depressive-like behavior in the forced swim test, and resulted in a reduction of cell proliferation in the dentate gyrus of the hippocampus. Finally, we showed that, contrary to the PKC inhibitors, the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced risk-taking behavior and induced an antidepressant-like effect. Taken together, these findings support the involvement of PKC in regulating opposite facets of bipolar disorder, and emphasize a major role for PKC in this disease.Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2012; 43. DOI:10.1016/j.pnpbp.2012.11.015 · 4.03 Impact Factor