Metabolic, hormonal and stress-related molecular changes in<i>post-mortem</i>pituitary glands from schizophrenia subjects

Krishnamurthy, D.; Harris, Laura W.; Levin, Yishai; Koutroukides, Theodoros; Rahmoune, Hassan; Pietsch, Sandra; Vanattou-Saifoudine, Natacha; Leweke, F. Markus; Guest, Paul C.; Bahn, Sabine

doi:10.3109/15622975.2011.601759

Cited by 43 publications

(26 citation statements)

References 52 publications

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“…LC-MS E data were processed using the ProteinLynx Global Server v2.5 (Waters Corporation) and the Rosetta Elucidator v3.3 (Rosetta Biosoftware, Seattle, Wash., USA) for time and mass/charge alignment of the MS data as described previously [13]. The Mus musculus complete proteome FASTA sequence Integr8 database was used for the assignment of protein identities.…”

Section: Methodsmentioning

confidence: 99%

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

et al. 2016

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Despite the recent progress in psychiatric genetics, very few studies have focused on genetic risk factors in glial cells that, compared to neurons, can manifest different molecular pathologies underlying psychiatric disorders. In order to address this issue, we studied the effects of mutant disrupted in schizophrenia 1 (DISC1), a genetic risk factor for schizophrenia, in cultured primary neurons and astrocytes using an unbiased mass spectrometry-based proteomic approach. We found that selective expression of mutant DISC1 in neurons affects a wide variety of proteins predominantly involved in neuronal development (e.g., SOX1) and vesicular transport (Rab proteins), whereas selective expression of mutant DISC1 in astrocytes produces changes in the levels of mitochondrial (GDPM), nuclear (TMM43) and cell adhesion (ECM2) proteins. The present study demonstrates that DISC1 variants can perturb distinct molecular pathways in a cell type-specific fashion to contribute to psychiatric disorders through heterogenic effects in diverse brain cells.

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Section: Methodsmentioning

confidence: 99%

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

et al. 2016

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“…(Waters Corporation) and Rosetta Elucidator v.3.3. (Rosetta Biosoftware, Seattle, WA) for time and mass/ charge alignment of mass spectrometer data as described in Krishnamurthy et al (2012). The Rattus norvegicus and the Homo sapiens complete proteome fasta sequence Integr8 database were used for the assignment of protein identities.…”

Section: Human Post-mortem Brain Samplesmentioning

confidence: 99%

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Wesseling

Chan

Tsang

et al. 2013

Neuropsychopharmacol

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Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic-and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca 2 þ signaling (Ca 2 þ /calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca 2 þ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ.

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“…Additionally, perinatal and adolescent stressors are risk factors for schizophrenia [66]. Post-mortem studies also indicate that VP and HPA-axis associated constituents such as cortisol are differentially expressed in the pituitary gland of schizophrenia patients [67]. This study did not account for cortisol levels and therefore the effects of the HPA axis alteration were not accessed.…”

Section: Limitationsmentioning

confidence: 99%

Differential sensitivity of the Brattleboro rat to glutamatergic and dopaminergic perturbation

Lin¹,

Ambler²,

Billingslea³

et al. 2014

J Psychiatry Brain Funct

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Background: The vasopressin deficient Brattleboro (BRAT) rats have behavioral impairments which mimic those seen in other schizophrenia models. However, the mechanism by which vasopressin produces these behavioral abnormalities is unclear. Notably, elevations in dopamine signaling as well as reductions in glutamatergic signaling have been associated with behavioral impairments consistent with those observed in the BRAT rats. Therefore, a potential mechanism for vasopressin induces behavioral abnormalities could be through modulation of dopamine or glutamate signaling. Consequently, the aim of this study was to assess the modulatory function of vasopressin on dopamine and NMDA signaling. Methods: Single intraperitoneal injection of amphetamine (0.5 mg/kg), a dopamine agonist, and MK801 (0.25 mg/kg), a NMDA antagonist, were used to assess vasopressin (VP) modulatory activity on dopaminergic and glutamatergic pre-pulse inhibition of startle (PPI), social interaction and auditory event related potential (ERPs) impairments in BRAT and littermate control WT rats. Results: MK801-induced impairments were consistent and not significantly different between WT and BRAT rats suggesting minimal modulatory activity of vasopressin on NMDA signaling. In contrast, amphetamine-induced deficits were genotype dependent. In control animals, amphetamine caused a statistically significant deficit in PPI and social interaction whereas there was no effect in BRAT rats. Conversely, ERP components were unaltered in control rats, whereas N40 amplitude, evoked gamma power, and gamma signal to noise ratio were all elevated in BRAT rats. Conclusions:The ERP component analyses of BRAT rats treated with amphetamine suggest modulation of auditory information processing through interplay between dopaminergic and vasopressin. However, the behavioral and electrophysiological evidence presented here also suggest that vasopressin does not modulate glutamatergic signaling through NMDA receptors. Further evidence in necessary to determine the interaction between vasopressin and dopamine signaling and future studies are necessary to comprehend glutamatergic interactions with vasopressin that are not NMDA-mediated.

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Metabolic, hormonal and stress-related molecular changes inpost-mortempituitary glands from schizophrenia subjects

Abstract: Future studies on the molecules identified here may lead to new insights into schizophrenia pathophysiology and pave the way for translation of novel diagnostics for use in a clinical setting.

Cited by 43 publications

References 52 publications

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Differential sensitivity of the Brattleboro rat to glutamatergic and dopaminergic perturbation

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