Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

Vawter, Marquis P.; Weickert, Cynthia Shannon; Ferran, Erick; Matsumoto, Mitsuyuki; Overman, Kevin; Hyde, Thomas M.; Weinberger, Daniel R.; Bunney, William E.; Kleinman, Joel E.

doi:10.1023/b:nere.0000023611.99452.47

Cited by 89 publications

(71 citation statements)

References 45 publications

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“…Since synaptic perturbations may represent structural correlates of neuropsychiatric disorders (Penzes et al 2011) and dysregulated expression of neuroserpin has been found in schizophrenia (Hakak et al 2001;Vawter et al 2004;Brennand et al 2011;Wen et al 2014) we investigated neuroserpin levels in patients suffering from neuropsychiatric disorders. Neuroserpin protein levels were analyzed by quantitative Western blotting in post-mortem fusiform gyrus from subjects with idiopathic autism and controls as well as in post-mortem dorsolateral prefrontal cortex from subjects with chronic schizophrenia and control subjects with no history of psychiatric episodes.…”

Section: Unaltered Levels Of Neuroserpin In Brains From Autism and Scmentioning

confidence: 99%

“…Removal of Lynx1, a negative regulator of adult plasticity, leads to experience-dependent elevation of tPA and increased plasticity, a process blocked by administration of neuroserpin (Bukhari et al 2015). In addition to this direct evidence linking neuroserpin to synaptic function, translational data from schizophrenic patients, a disorder characterized by improper synaptic function, showed dysregulation of neuroserpin (Hakak et al 2001;Vawter et al 2004;Brennand et al 2011;Wen et al 2014), and mice with dysregulated expression of neuroserpin show selective reduction of locomotor activity in novel environments, anxiety-like response on the O-maze, and neophobic response to novel objects (Madani et al 2003). In this study, we demonstrate the essential role of neuroserpin in maintaining functional synapses in vivo.…”

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confidence: 92%

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The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

et al. 2017

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The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory.

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Section: Unaltered Levels Of Neuroserpin In Brains From Autism and Scmentioning

confidence: 99%

mentioning

confidence: 92%

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

et al. 2017

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“…Real-time quantitative PCR (Q-PCR) with SybrGreen dye was used to replicate the microarray results as previously described 42 on total RNA extracted from the DLPFC and anterior cingulate. Real-time quantitative Q-PCR was carried out in an Applied Biosystems 7000 sequence detection system (ABI, Foster City, CA, USA) according to the manufacturer's protocol for SybrGreen PCR using a 25 μl reaction volume and 5 μl of diluted cDNA template.…”

Section: Real Time Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

et al. 2006

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Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe pathophysiology of depression and mania is largely unknown leaving open a question of which cellular pathway(s) to investigate. Gene expression screening is a powerful method for probing alterations in neural functions in mood disorder. Examining gene expression profiles has been extremely useful for establishing different phenotypes in cancer. [1][2][3] Various microarray profiles in mood disorder have been reported that use different microarray platforms, analysis methodology, regional differences, agonal factors and brain pH. [4][5][6][7][8][9][10][11][12][13][14] Presumably, a substantial heterogeneity in the pathophysiology of mood disorder coupled with small sample sizes and small fold changes contributes to the lack of consistency among the findings. 15 In five microarray studies a broad mitochondrial dysfunction was reported in neuropsychiatric disorders. 10,11,14,[16][17][18] One study of bipolar disorder (BPD) focused on a broad set of mitochondrial-related gene expression and found that in general, mitochondrial gene expression was predominantly decreased in BPD compared to controls in the dorsolateral pre-frontal cortex (DLPFC) when using Stanley samples...

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“…In a microarray analysis, HINT1 mRNA expression was lower in the dorsolateral prefrontal cortex of patients who suffer from schizophrenic and bipolar disorder than healthy controls (Elashoff et al., 2007; Vawter et al., 2001, 2004). HINT1 is also associated with abuse of drugs, such as nicotine (Jackson et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

“…However, Varadarajulu and colleagues have reported that Hint1‐ KO mice showed increased anxiety‐like behavior (Varadarajulu et al., 2011). Additionally, the correlations between schizophrenia and HINT1 are sex specific (Chen et al., 2008; Jackson et al., 2012; Vawter et al., 2004), and nicotine‐mediated acute behavior changes also show different effects in males and females (Jackson et al., 2012). Nonetheless, it remains unknown whether HINT1 involved in the regulation of anxious and depressed behaviors under chronic immobilization stress is sex specific or haplo insufficient.…”

Section: Introductionmentioning

confidence: 99%

Effects of Hint1 deficiency on emotional‐like behaviors in mice under chronic immobilization stress

Sun

Liu

et al. 2017

Brain and Behavior

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BackgroundHistidine triad nucleotide‐binding protein 1 (HINT1) is regarded as a haplo‐insufficient tumor suppressor and is closely associated with diverse neuropsychiatric diseases. Moreover, HINT1 is related to gender‐specific acute behavior changes in schizophrenia and in response to nicotine. Stress has a range of molecular effects in emotional disorders, which can cause a reduction in brain‐derived neurotrophic factor (BDNF) expression in the hippocampus, resulting in hippocampal atrophy and neuronal cell loss.MethodsThis study examined the role of HINT1 deficiency in anxiety‐related and depression‐like behaviors and BDNF expression in the hippocampus under chronic immobilization stress, and investigated whether the sex‐specific and haplo‐insufficient effects exist in emotional‐like behaviors under the same condition.ResultsIn a battery of behavior tests, the results of the control group, not exposed to stress, showed that knockout (KO) and heterozygosity (HT) of Hint1 had anxiolytic‐like and antidepression‐like effects on the male and female mice. However, both male and female Hint1‐KO mice showed elevated anxiety‐related and antidepression‐like behavior under chronic immobilization stress; moreover, both male and female Hint1‐HT mice displayed elevated anxiety‐related behavior and increased depression‐like behavior under chronic immobilization stress. There were no significant differences in general locomotor activity between Hint1‐KO and ‐HT mice and their wild‐type (WT) littermates. Hint1‐KO mice under basal and chronic immobilization stress conditions expressed more BDNF in the hippocampus than did Hint1‐HT and WT mice; overall, there were no significant sex differences in emotional‐like behaviors of Hint1‐KO and ‐HT mice. Additionally, Hint1‐HT mice showed haplo‐insufficient effects on emotional‐like behaviors under basic conditions, rather than under chronic immobilization stress.ConclusionsBoth male and female HINT 1 KO and HT mice had a trend of anxiolytic‐like behavior and antidepression‐like behavior at control group. However, both male and female HINT1 KO mice showed elevated anxiety‐related and antidepression‐like behavior under chronic immobilization stress; moreover, both male and female HINT1 HT mice displayed elevated anxiety‐related behavior and increased depression‐like behavior under chronic immobilization stress.

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Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

Cited by 89 publications

References 45 publications

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

Effects of Hint1 deficiency on emotional‐like behaviors in mice under chronic immobilization stress

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