Expression of the NR2B‐NMDA receptor subunit and its Tbr‐1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia

Kristiansen, Lars V.; Patel, Sagar; Haroutunian, Vahram; Meador‐Woodruff, James H.

doi:10.1002/syn.20754

Cited by 74 publications

(60 citation statements)

References 59 publications

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“…Regional differences in molecular abnormalities in schizophrenia are consistently reported in the literature (Katsel et al, 2005a, b;Kristiansen et al, 2006Kristiansen et al, , 2010Oni-Orisan et al, 2008), and although the sets of changes we found differed by cortical region, each set is functionally similar, resulting in decreased signal integration in both regions. This differential expression pattern may be inherent to the physiological circuits and inputs for each region.…”

Section: Discussionsupporting

confidence: 76%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

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128

102

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Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3 0 -5 0 -cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK-and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC ¼ 36, DLPFC ¼ 35) and a comparison (ACC ¼ 33, DLPFC ¼ 31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK-and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK-and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK-and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.

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Section: Discussionsupporting

confidence: 76%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

Self Cite

128

102

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“…In a different study, we used an anti-calnexin antibody to capture ER microsomes from postmortem brain homogenate. We found decreased expression of PSD95 and GluN2B in the ER-enriched fraction (but no change in total levels), suggesting increased forward trafficking of NMDA receptor complexes from the ER (Kristiansen et al, 2010).…”

Section: Assessment Of Protein-protein Interactions In Postmortem Tismentioning

confidence: 59%

“…For example, one mechanism of diminished NMDA receptor expression could be retention (and degradation) of NMDA receptor complexes in the ER. Decreased expression of PSD95 and GluN2B was found in an ER-enriched fraction in DLPFC from subjects with schizophrenia (but no change in total levels), suggesting increased forward trafficking of NMDA receptor complexes from the ER (Kristiansen et al, 2010). These data suggest that the rate of turnover of NMDA receptor complexes may be altered, with a compensatory increase in trafficking to the synapse.…”

Section: Data From Post-synaptic Density 95 (Psd95)mentioning

confidence: 77%

“…Thus, we propose 'immunoisolation (II)' as a more accurate term to describe this technique. Popular capture media include protein A, protein G, or protein A/Glinked agarose or magnetic beads, with attachment of the primary antibody to the bead substrate (Kristiansen et al, 2010). The antibody-bead complex is incubated with the sample, and then the beads are isolated.…”

Section: Assessment Of Protein-protein Interactions In Postmortem Tismentioning

confidence: 99%

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Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

103

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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“…Recently, aberrant signaling of N-methyl-d-aspartate (NMDA)-glutamate has been associated with positive, negative and cognitive deficits in schizophrenia [29]. Postmortem brain studies have identified altered expression of the cluster of structural and signaling molecules of the postsynaptic density (PSD) which bind directly of the NR2 subunits of NMDA system [30], with adverse consequences on the NDMD-mediated trafficking, membrane expression and downstream signaling pathways.…”

Section: Nmda-glutamate Signaling and Curcuminmentioning

confidence: 99%

Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia?

Chiu¹,

Woodbury-Fariña²,

Terpstra³

et al. 2017

J Clin Epigenet

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While pharmacotherapy of second generation of atypical antipsychotics: clozapine, olanzapine, risperidol, quetiapine, ziprasidone, aripiprazole bring about significant improvement in the positive symptoms of schizophrenia [1], overall psychosocial outcomes in schizophrenia remain modest. Significant functional impairment related to negative symptoms (lack of volition, apathy, sociality, poverty of speech and affective flattening), active positive symptoms (delusions, hallucinations and bizarre behavioral disturbances) and neuro-cognition deficits, persists in 20-30% of patients with schizophrenia refractory to AbstractDespite advances in pharmacotherapy, schizophrenia continues to carry a high societal disease burden related to positive and negative symptoms, and neurocognitive deficits and severe functional impairment. Findings from epigenetics have yet to translate the epigenetics targets to efficacious drug therapy. We review the repertoire of CNS pharmacology of curcumin derived from Curcuma Longa, commonly known as "turmeric": the well-known curry extract. We highlight the body of evidence in support of the emerging role of curcumin as a panhistone deacetylase (HDAC) inhibitor regulating the expression of genes involved in inflammation and NMDA N-methyl-aspartic acid (NMDA)-glutamate systems, as related to schizophrenia. Based on the findings from translational studies of curcumin extracts, curcumin C-3 complex formulation (Supercurcumin TM ) and patented liposome-based curcumin (Lipocurc TM ), we propose that intravenous infusion of Lipocurc TM holds promise as the novel drug lead and preferred targeted brain delivery mode in reprogramming faculty epigenetics network and in remodeling restrictive chromatin configuration in schizophrenia. Phase II/Phase III epigenetics-biomarker-based randomized placebo-controlled trials in treatment resistant schizophrenia are warranted. Our approach of intravenous infusion of Lipocurc TM behaving as pan HDAC inhibitor represents a new paradigm of drug development in combining targeting epigenetics footprints with brain-specific drug delivery system in schizophrenia. Lipocurc TM can open the Pandora box in unexplored therapeutics vistas in modifying the phenotype of treatment resistant schizophrenia. [2]. Major breakthroughs in schizophrenia therapeutics are yet forthcoming. It becomes imperative to design molecular genetics and epigenetic tools to predict treatment responses, and to translate novel CNS drug targets for accelerating the development of new therapeutics for treatment refractory schizophrenia. Drug platforms require refinement of translational models of schizophrenia to catalyze clinical trials and to predict treatment responses. In the post-genomic era, deciphering the epigenetic code of the human genomes represents a major challenge in CNS disorders. A growing body of evidence supports dysregulation of epigenetics signaling: DNA methylation, histone modifications and microRNA, plays a significant role in schizophrenia [3][4][5]. Findings from studies of p...

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Expression of the NR2B‐NMDA receptor subunit and its Tbr‐1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia

Cited by 74 publications

References 59 publications

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia?

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