Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Saxena, Ashwini; Scaini, Giselli; Bavaresco, Daniela V.; Leite, Camila Ferreira; Valvassori, Samira S.; Carvalho, André F.; Quevedo, João

doi:10.1159/000480349

Cited by 67 publications

(86 citation statements)

References 175 publications

(217 reference statements)

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“…The mice that took longer to re-entrain normal sleepwake rhythms after circadian disruption also displayed greater quinpirole-induced hyperactivity, indicative of a more mania-like state, however depressive-like behavior (forced swim test) was not affected 137,138 . Based on these studies and human clinical data, the pathophysiology of environmental circadian disruption underlying bipolar mania may be via altered protein kinase c activity affecting neuronal signaling in frontal and limbic brain regions 139 .…”

Section: Circadian Rhythm Disruption and Bipolar Disordermentioning

confidence: 99%

Circadian rhythm disruption and mental health

et al. 2020

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Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light-dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.

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Section: Circadian Rhythm Disruption and Bipolar Disordermentioning

confidence: 99%

Circadian rhythm disruption and mental health

et al. 2020

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“…This association is further supported by the role of DAG in bipolar disorder-associated signalling. In mammalian models, DGK competes with PKC for binding to DAG, thereby regulating PKC activity, and dysregulation of the PKC signalling pathway has been widely demonstrated in bipolar disorder patient populations and following therapeutic treatment ( Sakai and Sakane, 2012 ; Saxena et al, 2017 ). Numerous studies have identified upregulated PKC activity in bipolar disorder patients ( Friedman et al, 1993 ; Wang and Friedman, 1996 ), with this activity being reduced by both lithium ( Friedman et al, 1993 ; Wang and Friedman, 1989 ) and VPA ( Ramadan et al, 2011 ; Watson et al, 1998 ) in animal models and patient studies ( Katsel et al, 2008 ; Soares and Mallinger, 1997 ; Wang et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum

Kelly

Sharma

Wilkinson

et al. 2018

Disease Models &Amp; Mechanisms

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Valproic acid (VPA) provides a common treatment for both epilepsy and bipolar disorder; however, common cellular mechanisms relating to both disorders have yet to be proposed. Here, we explore the possibility of a diacylglycerol kinase (DGK) playing a role in regulating the effect of VPA relating to the treatment of both disorders, using the biomedical model Dictyostelium discoideum. DGK enzymes provide the first step in the phosphoinositide recycling pathway, implicated in seizure activity. They also regulate levels of diacylglycerol (DAG), thereby regulating the protein kinase C (PKC) activity that is linked to bipolar disorder-related signalling. Here, we show that ablation of the single Dictyostelium dgkA gene results in reduced sensitivity to the acute effects of VPA on cell behaviour. Loss of dgkA also provides reduced sensitivity to VPA in extended exposure during development. To differentiate a potential role for this DGKA-dependent mechanism in epilepsy and bipolar disorder treatment, we further show that the dgkA null mutant is resistant to the developmental effects of a range of structurally distinct branched medium-chain fatty acids with seizure control activity and to the bipolar disorder treatment lithium. Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment. Thus, these experiments suggest that, in Dictyostelium, loss of DGKA attenuates a common cellular effect of VPA relating to both epilepsy and bipolar disorder treatments, and that a range of new compounds with this effect should be investigated as alternative therapeutic agents.This article has an associated First Person interview with the first author of the paper.

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“…Protein kinase C (PKC) has often been suggested as playing a key role in BD, as both lithium and valproate inhibit PKC signaling [88]. Thus, inhibitors of PKC have been considered as potential therapeutic agents [89].…”

Section: Discussionmentioning

confidence: 99%

A novel co-segregatingDCTN1splice site variant in a family with Bipolar Disorder may hold the key to understanding the etiology

Hallen

Cooper

2018

Preprint

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AbstractA novel co-segregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22+1G>T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150Glued protein (ct-p150Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.

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Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Cited by 67 publications

References 175 publications

Circadian rhythm disruption and mental health

Circadian rhythm disruption and mental health

Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum

A novel co-segregatingDCTN1splice site variant in a family with Bipolar Disorder may hold the key to understanding the etiology

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