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Athanas K.M.,Laboratory of Cellular Neuropathology | Mauney S.L.,Laboratory of Cellular Neuropathology | Woo T.U.W.,Laboratory of Cellular Neuropathology | Woo T.U.W.,Beth Israel Deaconess Medical Center | Woo T.U.W.,Harvard University
Schizophrenia Research | Year: 2015

The expression of the gene that encodes clusterin, a glycoprotein that has been implicated in the regulation of many cellular processes, has previously been found in gene expression profiling studies to be among the most significantly differentially expressed genes in pyramidal and parvalbumin-containing inhibitory neurons in the cerebral cortex in subjects with schizophrenia. In this study, we investigated whether clusterin may also be dysregulated at the protein level in schizophrenia subjects. We found that, although the intracellular amount of clusterin may be unchanged, the level of extracellular, secreted clusterin appears to be significantly increased in schizophrenia subjects. It is speculated that this finding may represent a neuroprotective response to pathophysiological events that underlie schizophrenia. © 2015 Elsevier B.V.

Pietersen C.Y.,Laboratory of Cellular Neuropathology | Pietersen C.Y.,Harvard University | Mauney S.A.,Laboratory of Cellular Neuropathology | Kim S.S.,Laboratory of Cellular Neuropathology | And 14 more authors.
Journal of Neurogenetics | Year: 2014

Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder. © 2014 Informa Healthcare USA, Inc.

Thermenos H.W.,Harvard University | Thermenos H.W.,Beth Israel Deaconess Medical Center | Thermenos H.W.,Massachusetts General Hospital | Juelich R.J.,Harvard University | And 24 more authors.
Schizophrenia Research | Year: 2016

Background: Deficits in working memory (WM) are a core feature of schizophrenia (SZ) and other psychotic disorders. We examined brain activity during WM in persons at clinical high risk (CHR) for psychosis. Methods: Thirty-seven CHR and 34 healthy control participants underwent functional MRI (fMRI) on a 3.0 T scanner while performing an N-back WM task. The sample included a sub-sample of CHR participants who had no lifetime history of treatment with psychotropic medications (n = 11). Data were analyzed using SPM8 (2-back > 0-back contrast). Pearson correlations between brain activity, symptoms, and WM performance were examined. Results: The total CHR group and medication-naive CHR sub-sample were comparable to controls in most demographic features and in N-back WM performance, but had significantly lower IQ. Relative to controls, medication-naïve CHR showed hyperactivity in the left parahippocampus (PHP) and the left caudate during performance of the N-back WM task. Relative to medication-exposed CHR, medication naïve CHR exhibited hyperactivity in the left caudate and the right dorsolateral prefrontal cortex (DLPFC). DLPFC activity was significantly negatively correlated with WM performance. PHP, caudate and DLPFC activity correlated strongly with symptoms, but results did not withstand FDR-correction for multiple comparisons. When all CHR participants were combined (regardless of medication status), only trend-level PHP hyperactivity was observed in CHR relative to controls. Conclusions: Medication-naïve CHR exhibit hyperactivity in regions that subserve WM. These regions are implicated in studies of schizophrenia and risk for psychosis. Results emphasize the importance of medication status in the interpretation of task - induced brain activity. © 2016 Elsevier B.V.

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