Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

128

102

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.

Section: Discussionsupporting

confidence: 71%

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

128

102

“…The protein levels are determined not only by the level of the mRNA that codifies it and its translation rate, but also by the folding efficiency of the protein itself, posttranslational modifications, binding with other components to form protein complexes, and the rate of protein degradation. Some of these events could modify protein levels without a change in mRNA expression (You and Yin, 2000;Kristiansen et al, 2006). In summary, our data support that in schizophrenia and mood disorders, glutamate receptor expression is altered in the medial temporal lobe.…”

Section: Limitations Of the Studysupporting

confidence: 67%

Abnormal Glutamate Receptor Expression in the Medial Temporal Lobe in Schizophrenia and Mood Disorders

Beneyto

Kristiansen

Oni-Orisan

et al. 2007

368

216

Pharmacological and anatomical evidence suggests that abnormal glutamate neurotransmission may be associated with the pathophysiology of schizophrenia and mood disorders. Medial temporal lobe structural alterations have been implicated in schizophrenia and to a lesser extent in mood disorders. To comprehensively examine the ionotropic glutamate receptors in these illnesses, we used in situ hybridization to determine transcript expression of N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate receptor subunits in the medial temporal lobe of subjects with schizophrenia, bipolar disorder (BD), or major depression (MDD). We used receptor autoradiography to assess changes in glutamate receptor binding in the same subjects. Our results indicate that there are region-and disorder-specific abnormalities in the expression of ionotropic glutamate receptor subunits in schizophrenia and mood disorders. We did not find any changes in transcript expression in the hippocampus. In the entorhinal cortex, most changes in glutamate receptor expression were associated with BD, with decreased GluR2, GluR3, and GluR6 mRNA expression. In the perirhinal cortex we detected decreased expression of GluR5 in all three diagnoses, of GluR1, GluR3, NR2B in both BD and MDD, and decreased NR1 and NR2A in BD and MDD, respectively. Receptor binding showed NMDA receptor subsites particularly affected in the hippocampus, where MK801 binding was reduced in schizophrenia and BD, and MDL105,519 and CGP39653 binding were increased in BD and MDD, respectively. In the hippocampus AMPA and kainate binding were not changed. We found no changes in the entorhinal and perirhinal cortices. These data suggest that glutamate receptor expression is altered in the medial temporal lobe in schizophrenia and the mood disorders. We propose that disturbances in glutamate-mediated synaptic transmission in the medial temporal lobe are important factors in the pathophysiology of these severe psychiatric illnesses.

“…In a smaller study (n ¼ 6 subjects with schizophrenia, n ¼ 10 controls) in situ hybridization analysis showed that the expression of PSD95 was significantly decreased in Brodmann area 9 of the prefrontal cortex but not in the hippocampus (Ohnuma et al, 2000). Using tissues from elderly subjects from the Bronx VA brain collection, PSD95 transcripts were increased, and PSD95 protein was decreased in the anterior cingulate cortex (Kristiansen et al, 2006). This finding was replicated in the ACC by the same group in a cohort with overlapping subjects, whereas no change in PSD95 protein was found in the DLPFC (Funk et al, 2009(Funk et al, , 2012.…”

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

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

103

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.