Hippocampal Complexin Proteins and Cognitive Dysfunction in Schizophrenia

Sawada, Ken; Barr, Alasdair M.; Nakamura, Masato; Arima, Kunimasa; Young, Clint; Dwork, Andrew J.; Falkai, Peter; Phillips, Anthony G.; Honer, William G.

doi:10.1001/archpsyc.62.3.263

Cited by 107 publications

(81 citation statements)

References 49 publications

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“…Evidence for synaptic dysfunction in psychiatric disorders Expression changes in many synaptic-associated proteins such as synaptophysin, complexin I and II, synaptosomal-associated protein (SNAP)-25 and syntaxin (for example Eastwood et al, 43 Sawada et al, 44 Owen et al 45 and Frankle et al 46 ) have been found in schizophrenia. In addition, these protein changes are in keeping with synaptic-associated roles for many of the recently described candidate genes for schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…23 Indeed, synaptic disturbance in schizophrenia is well described, involving both the pre-and postsynaptic machinery, and is considered a characteristic feature of this complex disorder. [24][25][26][27] However, mRNA may not be the most reliable method to use in order to gain insight into the underlying pathophysiology of schizophrenia, where abnormalities in gene function may or may not affect downstream protein expression. 28,29 To approach this issue, proteomic techniques have been used, on a complementary basis, to investigate the underlying molecular abnormalities in the cortex in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

et al. 2007

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There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P < 0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

et al. 2007

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“…CME is important for both presynaptic and postsynaptic functions and both functions have been implicated in schizophrenia [73][74][75] . In presynaptic axon terminals, CME is required for the retrieval of synaptic vesicle proteins following neurotransmitter release, and for the recycling of vesicles back to the reserve pool 7 .…”

Section: Altered Cme May Contribute To Synaptic Pathologymentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane-and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the CME interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes, and aberrant neurodevelopment are all influenced by CME, and that other cellular trafficking mechanisms previously linked to psychoses interact with CME in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of CME may offer fruitful opportunities for novel treatments of schizophrenia.

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“…Possibly a hypofunction of the glutamatergic NMDA receptor acting on long-term potentiation disturbs synaptic plasticity 70 . On the molecular level there is strong support for decreased synaptic plasticity, mainly affecting the expression of presynaptic vesicle proteins including the synaptosome-associated protein 25 (SNAP-25) and syntaxin forming the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex [71][72][73][74][75][76][77][78][79] . The trimeric SNARE complex is involved in membrane fusion and exocytosis of neurotransmitters.…”

Section: Schizophrenia As a Disorder Of Disturbed Synaptic Plasticitymentioning

confidence: 99%

“…A more consistent finding within the hippocampus is abnormal synaptic connectivity, as shown by decreased expression of the presynaptic proteins synapsin, synaptophysin and SNAP-25 73 . In addition, disturbances of complexins in the hippocampus were associated with the severity of ante-mortem cognitive impairment 78 . Further insights in disturbed synaptic plasticity provided a microarray study of the superior temporal cortex, showing that decreased expression of immune-related genes may affect synaptic strength and transmission 44 .…”

Section: Schizophrenia As a Disorder Of Disturbed Synaptic Plasticitymentioning

confidence: 99%

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

Schmitt

Reich‐Erkelenz²,

Gebicke‐Härter

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Schizophrenia is a severe neurobiological disease with genetic and environmental factors playing a role in the pathophysiology. Several brain regions have been implicated in the disease process and are connected in complex neuronal circuits. On the cellular and molecular level, affected connectivity between these regions, involving dysfunctional myelination of neuronal axons, as well as alterations on the synaptic level and energy metabolism of neurons leading to disturbances in synaptic plasticity are major findings in post-mortem studies. Microarray studies investigating genome-wide gene expression have contributed to the findings of alterations in complex pathways in relevant brain regions in schizophrenia. Moreover, first laser-capture microdissection studies allowed the investigation of gene expression in specific groups of neurons. However, it must be kept in mind that in post-mortem studies confounding effects of medication, mRNA quality as well as the capability of the brain for neuroplastic regenerative mechanisms in individuals with a lifetime history of schizophrenia may influence the complex pattern of alterations on the molecular level. Despite these limitations, hypothesis-free transcriptome studies in brain tissue from schizophrenia patients offer a unique possibility to learn more about underlying mechanisms, leading to new insights in the pathophysiology of the disease. A, et al. / Rev Psiq Clín. 2013;40(1):10-5 Keywords: Schizophrenia, gene expression, microarray, RT-PCR, in situ hybridization, brain regions. Schmitt ResumoEsquizofrenia é uma severa doença neurobiológica com fatores genéticos e ambientais desempenhando um papel na fisiopatologia. Diversas regiões cerebrais têm sido implicadas no processo da doença e estão conectadas em complexos circuitos neuronais. Nos níveis molecular e celular, a conectividade afetada entre essas regiões, envolvendo mielinização disfuncional dos axônios neuronais, bem como as alterações no nível sináptico e metabolismo energético levando a distúrbios na plasticidade sináptica, são os maiores achados em estudos post-mortem. Estudos de microarranjos investigando a expressão gênica contribuíram para os achados de alterações em vias complexas em regiões cerebrais relevantes na esquizofrenia. Além disso, estudos utilizando microdissecção e captura a laser permitiram a investigação da expressão gênica em grupos específicos de neurônios. Entretanto, deve ser mantido em mente que em estudos post-mortem, confusos efeitos de medicação, qualidade de RNAm, bem como capacidade de mecanismos regenerativos neuroplásticos do cérebro em indivíduos com história de vida de esquizofrenia, podem influenciar o complexo padrão de alterações no nível molecular. Apesar dessas limitações, estudos transcriptômicos livres de hipóteses em tecido cerebral de pacientes esquizofrênicos oferecem uma possibilidade única para aprender mais sobre os mecanismos subjacentes, levando a novas ópticas da fisiopatologia da doença. A, et al. / Rev Psiq Clín. 2013;40(1):10-5 Palavras-cha...

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Hippocampal Complexin Proteins and Cognitive Dysfunction in Schizophrenia

Abstract: The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Cited by 107 publications

References 49 publications

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

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