Cellular models to study bipolar disorder: A systematic review

Viswanath, Biju; Jose, Sam; Squassina, Alessio; Thirthalli, Jagadisha; Purushottam, Meera; Mukherjee, Odity; Vladimirov, Vladimir I.; Patrinos, George P.; Zompo, Maria Del; Jain, Sanjeev

doi:10.1016/j.jad.2015.05.037

Cited by 50 publications

(30 citation statements)

References 125 publications

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“…Prior studies have also found deficits in complex I from postmortem brain samples of SZ [5] and BD subjects [6]. Alterations in complex I subunit proteins and genes have also been reported in lymphoblastoid cell lines and fibroblasts from subjects with SZ [5] and BD [7]. …”

Section: Introductionmentioning

confidence: 92%

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

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Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA “common deletion” in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

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Section: Introductionmentioning

confidence: 92%

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

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“…These genes are indeed key nodes of several processes involved in the physiological functioning of the brain, and they are potentially related to BPD development [11,12,13]. These genes also link the old monoaminergic hypothesis (serotoninergic, glutamate and cholinergic neurotransmission) with the more recent hypotheses of altered neuroplasticity, neurodevelopment and neurodegeneration in psychiatric disorders (long-term potentiation pathway, calcium signaling pathway, as well as the biological processes involved in learning and memory and in the management of circadian rhythm) [14,15,16]. Figure 1 summarizes the processes likely influenced by the genes considered herein.…”

Section: Introductionmentioning

confidence: 99%

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Calabrò¹,

Mandelli²,

Crisafulli³

et al. 2016

Neuropsychobiology

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Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

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“…Cellular modeling in BD using lymphoblastoid cell lines, fibroblasts, olfactory neuronal epithelium and neurons reprogrammed from induced pluripotent stem cells (iPSCs) [16][17][18], has proven useful to understand its biological basis, and potential pathways have been identified, especially in cellular resilience-related mechanisms. The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium.…”

Section: Impaired Cellular Resiliencementioning

confidence: 99%

“…These alterations can explain several clinical features such as the progressive shortening of inter-episode interval with each recurrence occurring in consort with reduced probability of treatment response as the illness progresses. This hypothesis is supported by recent genetic studies in postmortem prefrontal cortex samples, which identified the EGR3 regulatory unit (regulon) that translates environmental stimuli into long-term changes in the brain to be robustly repressed in BD patients [15], further suggesting that an impaired response to stress influences BD risk.Cellular modeling in BD using lymphoblastoid cell lines, fibroblasts, olfactory neuronal epithelium and neurons reprogrammed from induced pluripotent stem cells (iPSCs) [16][17][18], has proven useful to understand its biological basis, and potential pathways have been identified, especially in cellular resilience-related mechanisms. The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium.…”

mentioning

confidence: 99%

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Pereira¹,

Resende²,

Morais³

et al. 2017

IJCNMH

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Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca 2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the "MAM hypothesis" for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity. Bipolar DisorderBD is a chronic psychiatric illness with a remitting course, affecting 2.4% of the general population [1], characterized by mood swings between manic and depressive states that result in cognitive and functional impairments, high health care costs and premature mortality [2,3]. BD is the sixth leading cause of disability worldwide responsible for loss of more disability-adjusted life-years than all forms of cancer and major neurological conditions [4]. BD is associated with greatly impaired quality of life and increased physical health burden [5]. Moreover, BD patients tend to have high rates of divorce, unemployment, drug abuse and crime as consequence of impaired social cognition, and its impact on patients can be devastating, with approximately 23% of patients with BD reported having suicide attempts [6]. Moreover, individuals with BD diagnosis have a high risk of medical comorbidities such as metabolic (diabetes, obesity and metabolic syndrome) and cardiovascular disorders [7].Current knowl...

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Cellular models to study bipolar disorder: A systematic review

Cited by 50 publications

References 125 publications

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

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