Cellular Plasticity Cascades: Genes-To-Behavior Pathways in Animal Models of Bipolar Disorder

College of Pharmacy, Duluth, University of Minnesota, 55812, USA.
Biological Psychiatry (Impact Factor: 10.26). 07/2006; 59(12):1160-71. DOI: 10.1016/j.biopsych.2005.11.004
Source: PubMed


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.

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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). "
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    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 · 4.01 Impact Factor
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    • "A recent genome-wide association study of bipolar disorders (BD), which is another chronic major mental illness composed of recurrent episodic mood disturbances ranging from mania to severe depression, revealed that most of the highly significant associations were implicated in signaling cascades of plasticity [46]. It has been proposed that abnormalities in neuroplasticity lead to maladaptive developments in neural circuits, affecting the information processing that mediates various facets of BD symptomatology [47, 48]. Another study using peripheral biomarkers suggested that BD patients show increased oxidative stress and decreased neuron-specific endolase, a neuronal glycolytic enzyme known to mediate neuroplastic pathways and cell survival [49]. "
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    ABSTRACT: There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may be associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression and anxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway. The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing the antioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent work on oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementioned mood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactive nitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect against neuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depression or anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression and anxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.
    Current Neuropharmacology 03/2014; 12(2):108-19. DOI:10.2174/1570159X11666131120231448 · 3.05 Impact Factor
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    • "Acute and chronic stress could overload an already vulnerable system that might have been balanced by compensatory mechanism. Commonly used mood-stabilizing medications, including lithium, valproic acid, and tricyclic antidepressants act on proteins in the ERK/MAPK signaling cascades and also regulate gene expression (60–63). For example, valproic acid up-regulates GADD45A, a gene identified in our study (64). "
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    ABSTRACT: Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.
    Frontiers in Psychiatry 11/2013; 4:154. DOI:10.3389/fpsyt.2013.00154
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