Mitochondria, Synaptic Plasticity, And Schizophrenia

Ben‐Shachar, Dorit; Laifenfeld, Daphna

doi:10.1016/s0074-7742(04)59011-6

Cited by 164 publications

(92 citation statements)

References 154 publications

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“…The Ca 2+ -buffering function of mitochondria is particularly important in the nervous system in that long neuronal processes require local Ca 2+ stores in proximity to cope with transient and local changes in Ca 2+ induced by various neuronal activities (11). As such, we test if loss of DISC1 function has an impact on Ca 2+ -buffering capacity of mitochondria.…”

Section: Disc1-mitofilin Complex In Mitochondriamentioning

confidence: 99%

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Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin

Park

Jeong

Lee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

137

121

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Disrupted-in-schizophrenia 1 (DISC1) has emerged as a schizophrenia-susceptibility gene affecting various neuronal functions. In this study, we characterized Mitofilin, a mitochondrial inner membrane protein, as a mediator of the mitochondrial function of DISC1. A fraction of DISC1 was localized to the inside of mitochondria and directly interacts with Mitofilin. A reduction in DISC1 function induced mitochondrial dysfunction, evidenced by decreased mitochondrial NADH dehydrogenase activities, reduced cellular ATP contents, and perturbed mitochondrial Ca 2+ dynamics. In addition, deficiencies in DISC1 and Mitofilin induced a reduction in mitochondrial monoamine oxidase-A activity. The mitochondrial dysfunctions evoked by the deficiency of DISC1 were partially phenocopied by an overexpression of truncated DISC1 that is associated with schizophrenia in human. DISC1 deficiencies induced the ubiquitination of Mitofilin, suggesting that DISC1 is critical for the stability of Mitofilin. Finally, the mitochondrial dysfunction induced by DISC1 deficiency was partially reversed by coexpression of Mitofilin, confirming a functional link between DISC1 and Mitofilin for the normal mitochondrial function. According to these results, we propose that DISC1 plays essential roles for mitochondrial function in collaboration with a mitochondrial interacting partner, Mitofilin.IMMT | mitochondrial dysfunctions | hyperdopaminergia | calcium buffering | psychiatric disorders

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Section: Disc1-mitofilin Complex In Mitochondriamentioning

confidence: 99%

“…Intriguingly, mitochondrial dysfunction has been found to be associated with various psychiatric disorders, including schizophrenia (11). For example, Maurer et al (12) reported a deficit in the process of oxidative phosphorylation in the postmortem brains of patients with schizophrenia.…”

mentioning

confidence: 99%

Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin

Park

Jeong

Lee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

137

121

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“…Previous studies have shown that both calcineurin (Shibasaki et al, 1997) and RCAN (Chang and Min, 2005) proteins can localize to mitochondria. Furthermore, substantial experimental data indicate that mitochondrial activities can influence synaptic plasticity (Ben-Shachar and Laifenfeld, 2004;Jonas, 2006;Mattson, 2006). Whether RCAN1 and calcineurin localized to mitochondria are involved in this process remains to be determined.…”

Section: Specific Pools Of Calcineurin Are More Active In the Hippocamentioning

confidence: 99%

The Down Syndrome Critical Region Protein RCAN1 Regulates Long-Term Potentiation and Memory via Inhibition of Phosphatase Signaling

Hoeffer¹,

Dey²,

Sachan³

et al. 2007

J. Neurosci.

102

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Regulator of calcineurin 1 (RCAN1/MCIP1/DSCR1) regulates the calmodulin-dependent phosphatase calcineurin. Because it is located on human chromosome 21, RCAN1 has been postulated to contribute to mental retardation in Down syndrome and has been reported to be associated with neuronal degeneration in Alzheimer's disease. The studies herein are the first to assess the role of RCAN1 in memory and synaptic plasticity by examining the behavioral and electrophysiological properties of RCAN1 knock-out mice. These mice exhibit deficits in spatial learning and memory, reduced associative cued memory, and impaired late-phase long-term potentiation (L-LTP), phenotypes similar to those of transgenic mice with increased calcineurin activity. Consistent with this, the RCAN1 knock-out mice display increased enzymatic calcineurin activity, increased abundance of a cleaved calcineurin fragment, and decreased phosphorylation of the calcineurin substrate dopamine and cAMP-regulated phosphoprotein-32. We propose a model in which RCAN1 plays a positive role in L-LTP and memory by constraining phosphatase signaling.

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“…Most probably, higher ROS concentrations are not properly processed in early schizophrenia patients because key processes of stress response such as the purine catabolism are disturbed (30), leading to DNA damage, impaired energy production, altered gene and protein expression and, finally, in apoptosis and cell death, together leading to faulty neuronal plasticity, and perturbed neurotransmission. Such processes may start during neurodevelopment in schizophrenia and coincide with manifestation of symptoms during early adulthood (3,33).…”

mentioning

confidence: 99%

Oxidative Stress in Schizophrenia: Pathogenetic and Therapeutic Implications

Yao

Reddy²

2011

Antioxidants & Redox Signaling

111

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Over a century, a wide-ranging variety of pathophysiological models and causal hypotheses have been conceptualized for schizophrenia. One among these is the role for free radical-mediated pathology in schizophrenia, indicating impaired antioxidant defense system (AODS) and presence of oxidative stress in patients with schizophrenia. For the past two decades, the whole investigative domain of AODS and oxidative stress has broadened to include the wider AODS components, direct central nervous system assays of AODS, chemical imaging studies, proteomics, genetics of AODS, and, of importance to sufferers of schizophrenia, antioxidant therapeutics. These are some of the perspectives that are reviewed by several articles in this Forum. Overall, there has been growing recognition of the importance of oxidative stress in the pathophysiology of schizophrenia and in treatment-related side effects. The totality of the evidence from biochemistry, metabolomics, proteomics, genetics, and in vivo brain imaging points to the presence of multifarious abnormalities in the AODS and redox signaling in schizophrenia.

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Mitochondria, Synaptic Plasticity, And Schizophrenia

Cited by 164 publications

References 154 publications

Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin

Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin

The Down Syndrome Critical Region Protein RCAN1 Regulates Long-Term Potentiation and Memory via Inhibition of Phosphatase Signaling

Oxidative Stress in Schizophrenia: Pathogenetic and Therapeutic Implications

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