Abnormal synaptic plasticity and impaired cognition in schizophrenia

Schizophrenia(SCZ)is a severe mental illness that affects several brain domains with relation to cognition and behaviour.SCZ symptoms are typically classified into three categories,namely,positive,negative,and cognitive.The etiology of SCZ is thought to be multifactorial and poorly understood.Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ.Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ.Many factors,including synaptic structure changes,aberrant expression of plasticityrelated genes,and abnormal synaptic transmission,may influence synaptic plasticity and play vital roles in SCZ.In this article,we briefly summarize the morphology of the synapse,the neurobiology of synaptic plasticity,and the role of synaptic plasticity,and review potential mechanisms underlying abnormal synaptic plasticity in SCZ.These abnormalities involve dendritic spines,postsynaptic density,and long-term potentiation-like plasticity.We also focus on cognitive dysfunction,which reflects impaired connectivity in SCZ.Additionally,the potential targets for the treatment of SCZ are discussed in this article.Therefore,understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.

CPEB1,a novel risk gene in recent-onset schizophrenia,contributes to mitochondrial complex I defect caused by a defective provirus ERVWE1

BACKGROUND Schizophrenia afflicts 1%of the world population.Clinical studies suggest that schizophrenia patients may have an imbalance of mitochondrial energy metabolism via inhibition of mitochondrial complex I activity.Moreover,recent studies have shown that ERVWE1 is also a risk factor for schizophrenia.Nevertheless,there is no available literature concerning the relationship between complex I deficits and ERVWE1 in schizophrenia.Identifying risk factors and blood-based biomarkers for schizophrenia may provide new guidelines for early interventions and prevention programs.AIM To address novel potential risk factors and the underlying mechanisms of mitochondrial complex I deficiency caused by ERVWE1 in schizophrenia.METHODS Quantitative polymerase chain reaction(qPCR)and enzyme-linked immunosorbent assay were used to detect differentially expressed risk factors in blood samples.Clinical statistical analyses were performed by median analyses and Mann-Whitney U analyses.Spearman’s rank correlation was applied to examine the correlation between different risk factors in blood samples.qPCR,western blot analysis,and luciferase assay were performed to confirm the relationship among ERVWE1,cytoplasmic polyadenylation element-binding protein 1(CPEB1),NADH dehydrogenase ubiquinone flavoprotein 2(NDUFV2),and NDUFV2 pseudogene(NDUFV2P1).The complex I enzyme activity microplate assay was carried out to evaluate the complex I activity induced by ERVWE1.RESULTS Herein,we reported decreasing levels of CPEB1 and NDUFV2 in schizophrenia patients.Further studies showed that ERVWE1 was negatively correlated with CPEB1 and NDUFV2 in schizophrenia.Moreover,NDUFV2P1 was increased and demonstrated a significant positive correlation with ERVWE1 and a negative correlation with NDUFV2 in schizophrenia.In vitro experiments disclosed that ERVWE1 suppressed NDUFV2 expression and promoter activity by increasing NDUFV2P1 level.The luciferase assay revealed that ERVWE1 could enhance the promoter activity of NDUFV2P1.Additionally,ERVWE1 downregulated the expression of CPEB1 by suppressing the promoter activity,and the 400 base pair sequence at the 3′terminus of the promoter was the minimum sequence required.Advanced studies showed that CPEB1 participated in regulating the NDUFV2P1/NDUFV2 axis mediated by ERVWE1.Finally,we found that ERVWE1 inhibited complex I activity in SH-SY5Y cells via the CPEB1/NDUFV2P1/NDUFV2 signaling pathway.CONCLUSION In conclusion,CPEB1 and NDUFV2 might be novel potential blood-based biomarkers and pathogenic factors in schizophrenia.Our findings also reveal a novel mechanism of ERVWE1 in the etiology of schizophrenia.