Publications by authors named "Robert E Mccullumsmith"

83 Publications

mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain.

Mol Psychiatry 2021 May 14. Epub 2021 May 14.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.

The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.
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http://dx.doi.org/10.1038/s41380-021-01135-9DOI Listing
May 2021

Activation of acid-sensing ion channels by carbon dioxide regulates amygdala synaptic protein degradation in memory reconsolidation.

Mol Brain 2021 May 7;14(1):78. Epub 2021 May 7.

Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, 38163, Memphis, TN, USA.

Reconsolidation has been considered a process in which a consolidated memory is turned into a labile stage. Within the reconsolidation window, the labile memory can be either erased or strengthened. Manipulating acid-sensing ion channels (ASICs) in the amygdala via carbon dioxide (CO) inhalation enhances memory retrieval and its lability within the reconsolidation window. Moreover, pairing CO inhalation with retrieval bears the reactivation of the memory trace and enhances the synaptic exchange of the calcium-impermeable AMPA receptors to calcium-permeable AMPA receptors. Our patch-clamp data suggest that the exchange of the AMPA receptors depends on the ubiquitin-proteasome system (UPS), via protein degradation. Ziram (50 µM), a ubiquitination inhibitor, reduces the turnover of the AMPA receptors. CO inhalation with retrieval boosts the ubiquitination without altering the proteasome activity. Several calcium-dependent kinases potentially involved in the CO-inhalation regulated memory liability were identified using the Kinome assay. These results suggest that the UPS plays a key role in regulating the turnover of AMPA receptors during CO inhalation.
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http://dx.doi.org/10.1186/s13041-021-00786-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106190PMC
May 2021

Deficits in pattern separation and dentate gyrus proliferation after rodent lateral fluid percussion injury.

IBRO Neurosci Rep 2021 Jun 3;10:31-41. Epub 2021 Feb 3.

Department of Neurosurgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.

It has been demonstrated that adult born granule cells are generated after traumatic brain injury (TBI). There is evidence that these newly generated neurons are aberrant and are poised to contribute to poor cognitive function after TBI. Yet, there is also evidence that these newly generated neurons are important for cognitive recovery. Pattern separation is a cognitive task known to be dependent on the function of adult generated granule cells. Performance on this task and the relation to dentate gyrus dysfunction after TBI has not been previously studied. Here we subjected Sprague Dawley rats to lateral fluid percussion injury or sham and tested them on the dentate gyrus dependent task pattern separation. At 2 weeks after injury, we examined common markers of dentate gyrus function such as GSK3ß phosphorylation, Ki-67 immunohistochemistry, and generation of adult born granule cells. We found that injured animals have deficits in pattern separation. We additionally found a decrease in proliferative capacity at 2 weeks indicated by decreased phosphorylation of GSK3ß and Ki-67 immunopositivity as compared to sham animals. Lastly we found an increase in numbers of new neurons generated during the pattern separation task. These findings provide evidence that dentate gyrus dysfunction may be an important contributor to TBI pathology.
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http://dx.doi.org/10.1016/j.ibneur.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019949PMC
June 2021

Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection.

Biomed Pharmacother 2021 Jun 25;138:111437. Epub 2021 Feb 25.

Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.

Hyperinflammatory response caused by infections such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) increases organ failure, intensive care unit admission, and mortality. Cytokine storm in patients with Coronavirus Disease 2019 (COVID-19) drives this pattern of poor clinical outcomes and is dependent upon the activity of the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and its downstream target gene interleukin 6 (IL6) which interacts with IL6 receptor (IL6R) and the IL6 signal transduction protein (IL6ST or gp130) to regulate intracellular inflammatory pathways. In this study, we compare transcriptomic signatures from a variety of drug-treated or genetically suppressed (i.e. knockdown) cell lines in order to identify a mechanism by which antidepressants such as fluoxetine demonstrate non-serotonergic, anti-inflammatory effects. Our results demonstrate a critical role for IL6ST and NF-kappaB Subunit 1 (NFKB1) in fluoxetine's ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19.
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http://dx.doi.org/10.1016/j.biopha.2021.111437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904450PMC
June 2021

Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach.

Sci Rep 2021 02 24;11(1):4495. Epub 2021 Feb 24.

Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Health Science Campus, Mail Stop #1007, 3000 Arlington Avenue, Toledo, OH, 43614-2598, USA.

The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.
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http://dx.doi.org/10.1038/s41598-021-84044-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904823PMC
February 2021

Using protein turnover to expand the applications of transcriptomics.

Sci Rep 2021 Feb 23;11(1):4403. Epub 2021 Feb 23.

Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.

RNA expression and protein abundance are often at odds when measured in parallel, raising questions about the functional implications of transcriptomics data. Here, we present the concept of persistence, which attempts to address this challenge by combining protein half-life data with RNA expression into a single metric that approximates protein abundance. The longer a protein's half-life, the more influence it can have on its surroundings. This data offers a valuable opportunity to gain deeper insight into the functional meaning of transcriptome changes. We demonstrate the application of persistence using schizophrenia (SCZ) datasets, where it greatly improved our ability to predict protein abundance from RNA expression. Furthermore, this approach successfully identified persistent genes and pathways known to have impactful changes in SCZ. These results suggest that persistence is a valuable metric for improving the functional insight offered by transcriptomics data, and extended application of this concept could advance numerous research fields.
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http://dx.doi.org/10.1038/s41598-021-83886-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902815PMC
February 2021

Similarities and dissimilarities between psychiatric cluster disorders.

Mol Psychiatry 2021 Jan 27. Epub 2021 Jan 27.

Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets/cohort availability, and challenges with data normalization. Here, using DisGeNET, a gene-disease associations database, we sought to expand such investigations in terms of number and types of diseases. In a top-down manner, we analyzed an unbiased cluster of 36 psychiatric disorders and comorbid conditions at biological pathway, cell-type, drug-target, and chromosome levels and deployed density index, a novel metric to quantify similarities (close to 1) and dissimilarities (close to 0) between these disorders at each level. At pathway level, we show that cognition and neurotransmission drive the similarity and are involved across all disorders, whereas immune-system and signal-response coupling (cell surface receptors, signal transduction, gene expression, and metabolic process) drives the dissimilarity and are involved with specific disorders. The analysis at the drug-target level supports the involvement of neurotransmission-related changes across these disorders. At cell-type level, dendrite-targeting interneurons, across all layers, are most involved. Finally, by matching the clustering pattern at each level of analysis, we showed that the similarity between the disorders is influenced most at the chromosomal level and to some extent at the cellular level. Together, these findings provide first insights into distinct cellular and molecular pathologies, druggable mechanisms associated with several psychiatric disorders and comorbid conditions and demonstrate that similarities between these disorders originate at the chromosome level and disperse in a bottom-up manner at cellular and pathway levels.
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http://dx.doi.org/10.1038/s41380-021-01030-3DOI Listing
January 2021

Role of Astrocytes in Major Neuropsychiatric Disorders.

Neurochem Res 2021 Jan 7. Epub 2021 Jan 7.

Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA.

Astrocytes are the primary homeostatic cells of the central nervous system, essential for normal neuronal development and function, metabolism and response to injury and inflammation. Here, we review postmortem studies examining changes in astrocytes in subjects diagnosed with the neuropsychiatric disorders schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BPD). We discuss the astrocyte-related changes described in the brain in these disorders and the potential effects of psychotropic medication on these findings. Finally, we describe emerging tools that can be used to study the role of astrocytes in neuropsychiatric illness.
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http://dx.doi.org/10.1007/s11064-020-03212-xDOI Listing
January 2021

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia.

Int J Mol Sci 2020 Nov 21;21(22). Epub 2020 Nov 21.

Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.
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http://dx.doi.org/10.3390/ijms21228823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700673PMC
November 2020

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases.

Int J Mol Sci 2020 Nov 17;21(22). Epub 2020 Nov 17.

Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
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http://dx.doi.org/10.3390/ijms21228679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698519PMC
November 2020

A role for endothelial NMDA receptors in the pathophysiology of schizophrenia.

Schizophr Res 2020 Nov 11. Epub 2020 Nov 11.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2020.10.004DOI Listing
November 2020

KEOPS complex expression in the frontal cortex in major depression and schizophrenia.

World J Biol Psychiatry 2020 Sep 29:1-10. Epub 2020 Sep 29.

Department of Neuroscience, University of Toledo, Toledo, OH, USA.

Objectives: Recently, the presence of a complete five subunit Kinase, Endopeptidase and Other Proteins of small Size (KEOPS) complex was confirmed in humans. The highly conserved KEOPS protein complex has established roles in tRNA modification, protein translation and telomere homeostasis in yeast, but little is known about KEOPS mRNA expression and function in human brain and disease. Here, we characterise KEOPS expression in post-mortem tissue from subjects diagnosed with major depression (MDD) and schizophrenia and assess whether KEOPS is associated with telomere length dysregulation in neuropsychiatric disorders.

Methods: We assessed mRNA expression of KEOPS complex subunits TP53RK, TPRKB, GON7, LAGE3, OSGEP, and OSGEP mitochondrial ortholog OSGEPL1 in the dorsolateral prefrontal cortex (DLPFC) of subjects with MDD, schizophrenia and matched non-psychiatrically ill controls ( = 20 per group) using qPCR. We conducted bioinformatic analysis using Kaleidoscope, data mining post-mortem transcriptomic datasets to characterise KEOPS expression in human brain. Finally, we assayed relative telomere length in the DLPFC using a qPCR-based assay and carried out correlation analysis with KEOPS subunit mRNA expression to determine if the KEOPS complex is associated with telomere length dysregulation in neuropsychiatric disorders.

Results: There were no significant changes in KEOPS mRNA expression in the DLPFC in MDD or schizophrenia compared to non-psychiatrically ill controls. Relative telomere length was not significantly altered in MDD or schizophrenia, nor was there an association between relative telomere length and KEOPS subunit gene expression in these subjects.

Conclusions: This study is the first to describe KEOPS complex expression in post-mortem brain and neuropsychiatric disorders. KEOPS subunit mRNA expression is not significantly altered in the DLPFC in MDD or schizophrenia. Unlike in yeast, the KEOPS complex does not appear to play a role in telomere length regulation in humans or in neuropsychiatric disorders.
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http://dx.doi.org/10.1080/15622975.2020.1821917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005497PMC
September 2020

Oxytocin's anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach.

Physiol Genomics 2020 09 18;52(9):401-407. Epub 2020 Aug 18.

University of Toledo, Department of Psychiatry, College of Medicine and Life Sciences, Toledo, Ohio.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1β and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.
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http://dx.doi.org/10.1152/physiolgenomics.00095.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877479PMC
September 2020

Consequences of NMDA receptor deficiency can be rescued in the adult brain.

Mol Psychiatry 2020 Aug 17. Epub 2020 Aug 17.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.
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http://dx.doi.org/10.1038/s41380-020-00859-4DOI Listing
August 2020

Combining Neurobehavioral Analysis and Photoaffinity Labeling to Understand Protein Targets of Methamphetamine in Casper Zebrafish.

ACS Chem Neurosci 2020 09 18;11(17):2761-2773. Epub 2020 Aug 18.

Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States.

Photoaffinity labeling (PAL) remains one of the most widely utilized methods of determining protein targets of drugs. Although useful, the scope of this technique has been limited to applications because of the inability of UV light to penetrate whole organisms. Herein, pigment-free Casper zebrafish were employed to allow PAL. A methamphetamine-related phenethylamine PAL probe, designated here as , demonstrated dose-dependent effects on behavior similar to methamphetamine and permitted concentration-dependent labeling of protein binding partners. Click chemistry was used to analyze binding partners via fluoroimaging. Conjugation to a biotin permitted streptavidin pull-down and proteomic analysis to define direct binding partners of the methamphetamine probe. Bioinformatic analysis revealed the probe was chiefly bound to proteins involved in phagocytosis and mitochondrial function. Future applications of this experimental paradigm combining examination of drug-protein binding interactions alongside neurobehavioral readouts via PAL will significantly enhance our understanding of drug targets, mechanism(s) of action, and toxicity/lethality.
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http://dx.doi.org/10.1021/acschemneuro.0c00416DOI Listing
September 2020

Identification of new drug treatments to combat COVID19: A signature-based approach using iLINCS.

Res Sq 2020 Apr 30. Epub 2020 Apr 30.

The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. As no vaccine or drugs are currently approved to specifically treat COVID-19, identification of effective therapeutics is crucial to treat the afflicted and limit disease spread. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and signatures of coronavirus-infected cell lines to identify therapeutics with concordant signatures and discordant signatures, respectively. Our findings include three FDA approved drugs that have established antiviral activity, including protein kinase inhibitors, providing a promising new category of candidates for COVID-19 interventions.
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http://dx.doi.org/10.21203/rs.3.rs-25643/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336712PMC
April 2020

Signature-based approaches for informed drug repurposing: targeting CNS disorders.

Neuropsychopharmacology 2021 01 30;46(1):116-130. Epub 2020 Jun 30.

Department of Neurosciences, University of Toledo, Toledo, OH, USA.

CNS disorders, and in particular psychiatric illnesses, lack definitive disease-altering therapeutics. The limited understanding of the mechanisms driving these illnesses with the slow pace and high cost of drug development exacerbates this issue. For these reasons, drug repurposing - both a less expensive and time-efficient practice compared to de novo drug development - has been a promising strategy to overcome the paucity of treatments available for these debilitating disorders. While empirical drug-repurposing has been a routine practice in clinical psychiatry, innovative, informed, and cost-effective repurposing efforts using big data ("omics") have been designed to characterize drugs by structural and transcriptomic signatures. These strategies, in conjunction with ontological integration, provide an important opportunity to address knowledge-based challenges associated with drug development for CNS disorders. In this review, we discuss various signature-based in silico approaches to drug repurposing, its integration with multiple omics platforms, and how this data can be used for clinically relevant, evidence-based drug repurposing. These tools provide an exciting translational avenue to merge omics-based drug discovery platforms with patient-specific disease signatures, ultimately facilitating the identification of new therapies for numerous psychiatric disorders.
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http://dx.doi.org/10.1038/s41386-020-0752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688959PMC
January 2021

Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor α.

J Biol Chem 2020 07 13;295(29):9804-9822. Epub 2020 May 13.

Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator-activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 () and adrenoreceptor β 3 (). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.
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http://dx.doi.org/10.1074/jbc.RA120.013700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380202PMC
July 2020

Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter.

Mol Psychiatry 2020 May 4. Epub 2020 May 4.

Neuro-Aging & Viro-Immunotherapy, Center for Neurosciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

The astrocytic cystine/glutamate antiporter system x represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system x, xCT (xCT mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT mice. A proteomic and kinomic screen of the striatum of xCT mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system x plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.
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http://dx.doi.org/10.1038/s41380-020-0751-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609546PMC
May 2020

Adenosine Kinase Expression in the Frontal Cortex in Schizophrenia.

Schizophr Bull 2020 04;46(3):690-698

Department of Neuroscience, University of Toledo, Toledo, OH.

The adenosine hypothesis of schizophrenia posits that reduced availability of the neuromodulator adenosine contributes to dysregulation of dopamine and glutamate transmission and the symptoms associated with schizophrenia. It has been proposed that increased expression of the enzyme adenosine kinase (ADK) may drive hypofunction of the adenosine system. While animal models of ADK overexpression support such a role for altered ADK, the expression of ADK in schizophrenia has yet to be examined. In this study, we assayed ADK gene and protein expression in frontocortical tissue from schizophrenia subjects. In the dorsolateral prefrontal cortex (DLPFC), ADK-long and -short splice variant expression was not significantly altered in schizophrenia compared to controls. There was also no significant difference in ADK splice variant expression in the frontal cortex of rats treated chronically with haloperidol-decanoate, in a study to identify the effect of antipsychotics on ADK gene expression. ADK protein expression was not significantly altered in the DLPFC or anterior cingulate cortex (ACC). There was no significant effect of antipsychotic medication on ADK protein expression in the DLPFC or ACC. Overall, our results suggest that increased ADK expression does not contribute to hypofunction of the adenosine system in schizophrenia and that alternative mechanisms are involved in dysregulation of this system in schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbz086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147579PMC
April 2020

A bioinformatic inquiry of the EAAT2 interactome in postmortem and neuropsychiatric datasets.

Schizophr Res 2020 Mar 17. Epub 2020 Mar 17.

Department of Neurosciences, University of Toledo, Toledo, OH, USA. Electronic address:

Altered expression and localization of the glutamate transporter EAAT2 is found in schizophrenia and other neuropsychiatric (major depression, MDD) and neurological disorders (amyotrophic lateral sclerosis, ALS). However, the EAAT2 interactome, the network of proteins that physically or functionally interact with EAAT2 to support its activity, has yet to be characterized in severe mental illness. We compiled a list of "core" EAAT2 interacting proteins. Using Kaleidoscope, an R-shiny application, we data mined publically available postmortem transcriptome datasets to determine whether components of the EAAT2 interactome are differentially expressed in schizophrenia and, using Reactome, identify which interactome-associated biological pathways are altered. Overall, these "look up" studies highlight region-specific, primarily frontal cortex (dorsolateral prefrontal cortex and anterior cingulate cortex), changes in the EAAT2 interactome and implicate altered metabolism pathways in schizophrenia. Pathway analyses also suggest that perturbation of components of the EAAT2 interactome in animal models of antipsychotic administration impact metabolism. Similar changes in metabolism pathways are seen in ALS, in addition to altered expression of many components of the EAAT2 interactome. However, although EAAT2 expression is altered in a postmortem MDD dataset, few other components of the EAAT2 interactome are changed. Thus, "look up" studies suggest region- and disease-relevant biological pathways related to the EAAT2 interactome that implicate glutamate reuptake perturbations in schizophrenia, while providing a useful tool to exploit "omics" datasets.
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http://dx.doi.org/10.1016/j.schres.2020.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494586PMC
March 2020

Pioglitazone improves working memory performance when administered in chronic TBI.

Neurobiol Dis 2019 12 9;132:104611. Epub 2019 Sep 9.

Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, United States of America; Department of Neurology and Rehabilitation Medicine, University of Cincinnati, United States of America.

Traumatic brain injury (TBI) is a leading cause of long-term disability in the United States. Even in comparatively mild injuries, cognitive and behavioral symptoms can persist for years, and there are currently no established strategies for mitigating symptoms in chronic injury. A key feature of TBI-induced damage in acute and chronic injury is disruption of metabolic pathways. As neurotransmission, and therefore cognition, are highly dependent on the supply of energy, we hypothesized that modulating metabolic activity could help restore behavioral performance even when treatment was initiated weeks after TBI. We treated rats with pioglitazone, a FDA-approved drug for diabetes, beginning 46 days after lateral fluid percussion injury and tested working memory performance in the radial arm maze (RAM) after 14 days of treatment. Pioglitazone treated TBI rats performed significantly better in the RAM test than untreated TBI rats, and similarly to control animals. While hexokinase activity in hippocampus was increased by pioglitazone treatment, there was no upregulation of either the neuronal glucose transporter or hexokinase enzyme expression. Expression of glial markers GFAP and Iba-1 were also not influenced by pioglitazone treatment. These studies suggest that targeting brain metabolism, in particular hippocampal metabolism, may be effective in alleviating cognitive symptoms in chronic TBI.
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http://dx.doi.org/10.1016/j.nbd.2019.104611DOI Listing
December 2019

Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia.

Mol Omics 2019 06;15(3):173-188

Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Brussels, Belgium.

Protein kinases orchestrate signal transduction pathways involved in central nervous system functions ranging from neurodevelopment to synaptic transmission and plasticity. Abnormalities in kinase-mediated signaling are involved in the pathophysiology of neurological disorders, including neuropsychiatric disorders. Here, we expand on the hypothesis that kinase networks are dysregulated in schizophrenia. We investigated changes in serine/threonine kinase activity in cortical excitatory neurons differentiated from induced pluripotent stem cells (iPSCs) from a schizophrenia patient presenting with a 4 bp mutation in the disrupted in schizophrenia 1 (DISC1) gene and a corresponding control. Using kinome peptide arrays, we demonstrate large scale abnormalities in DISC1 cells, including a global depression of serine/threonine kinase activity, and changes in activity of kinases, including AMP-activated protein kinase (AMPK), extracellular signal-regulated kinases (ERK), and thousand-and-one amino acid (TAO) kinases. Using isogenic cell lines in which the DISC1 mutation is either introduced in the control cell line, or rescued in the schizophrenia cell line, we ascribe most of these changes to a direct effect of the presence of the DISC1 mutation. Investigating the gene expression signatures downstream of the DISC1 kinase network, and mapping them on perturbagen signatures obtained from the Library of Integrated Network-based Cellular Signatures (LINCS) database, allowed us to propose novel drug targets able to reverse the DISC1 kinase dysregulation gene expression signature. Altogether, our findings provide new insight into abnormalities of kinase networks in schizophrenia and suggest possible targets for disease intervention.
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http://dx.doi.org/10.1039/c8mo00173aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563817PMC
June 2019

Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia.

Sci Rep 2019 03 25;9(1):5087. Epub 2019 Mar 25.

Department of Neurosciences, University of Toledo, Toledo, OH, 43614, USA.

Converging evidence suggests bioenergetic defects contribute to the pathophysiology of schizophrenia and may underlie cognitive dysfunction. The transport and metabolism of lactate energetically couples astrocytes and neurons and supports brain bioenergetics. We examined the concentration of lactate in postmortem brain (dorsolateral prefrontal cortex) in subjects with schizophrenia, in two animal models of schizophrenia, the GluN1 knockdown mouse model and mutant disrupted in schizophrenia 1 (DISC1) mouse model, as well as inducible pluripotent stem cells (iPSCs) from a schizophrenia subject with the DISC1 mutation. We found increased lactate in the dorsolateral prefrontal cortex (p = 0.043, n = 16/group) in schizophrenia, as well as in frontal cortical neurons differentiated from a subject with schizophrenia with the DISC1 mutation (p = 0.032). We also found a decrease in lactate in mice with induced expression of mutant human DISC1 specifically in astrocytes (p = 0.049). These results build upon the body of evidence supporting bioenergetic dysfunction in schizophrenia, and suggests changes in lactate are a key feature of this often devastating severe mental illness.
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http://dx.doi.org/10.1038/s41598-019-41572-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433855PMC
March 2019

Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments.

Mol Neurobiol 2019 Jun 18;56(6):4492-4517. Epub 2018 Oct 18.

Department of Neuroscience, University of Toledo, Toledo, OH, USA.

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n = 16) and control (n = 16) and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens, may be employed to identify novel treatment strategies for schizophrenia and related diseases.
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http://dx.doi.org/10.1007/s12035-018-1390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584383PMC
June 2019

Role of glutamatergic system and mesocorticolimbic circuits in alcohol dependence.

Prog Neurobiol 2018 12 11;171:32-49. Epub 2018 Oct 11.

Department of Pharmacology and Experimental Therapeutics, University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA. Electronic address:

Emerging evidence demonstrates that alcohol dependence is associated with dysregulation of several neurotransmitters. Alterations in dopamine, glutamate and gamma-aminobutyric acid release are linked to chronic alcohol exposure. The effects of alcohol on the glutamatergic system in the mesocorticolimbic areas have been investigated extensively. Several studies have demonstrated dysregulation in the glutamatergic systems in animal models exposed to alcohol. Alcohol exposure can lead to an increase in extracellular glutamate concentrations in mesocorticolimbic brain regions. In addition, alcohol exposure affects the expression and functions of several glutamate receptors and glutamate transporters in these brain regions. In this review, we discussed the effects of alcohol exposure on glutamate receptors, glutamate transporters and glutamate homeostasis in each area of the mesocorticolimbic system. In addition, we discussed the genetic aspect of alcohol associated with glutamate and reward circuitry. We also discussed the potential therapeutic role of glutamate receptors and glutamate transporters in each brain region for the treatment of alcohol dependence. Finally, we provided some limitations on targeting the glutamatergic system for potential therapeutic options for the treatment alcohol use disorders.
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http://dx.doi.org/10.1016/j.pneurobio.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261463PMC
December 2018

Neurotransmitter changes after traumatic brain injury: an update for new treatment strategies.

Mol Psychiatry 2019 07 13;24(7):995-1012. Epub 2018 Sep 13.

Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.

Traumatic brain injury (TBI) is a pervasive problem in the United States and worldwide, as the number of diagnosed individuals is increasing yearly and there are no efficacious therapeutic interventions. A large number of patients suffer with cognitive disabilities and psychiatric conditions after TBI, especially anxiety and depression. The constellation of post-injury cognitive and behavioral symptoms suggest permanent effects of injury on neurotransmission. Guided in part by preclinical studies, clinical trials have focused on high-yield pathophysiologic mechanisms, including protein aggregation, inflammation, metabolic disruption, cell generation, physiology, and alterations in neurotransmitter signaling. Despite successful treatment of experimental TBI in animal models, clinical studies based on these findings have failed to translate to humans. The current international effort to reshape TBI research is focusing on redefining the taxonomy and characterization of TBI. In addition, as the next round of clinical trials is pending, there is a pressing need to consider what the field has learned over the past two decades of research, and how we can best capitalize on this knowledge to inform the hypotheses for future innovations. Thus, it is critically important to extend our understanding of the pathophysiology of TBI, particularly to mechanisms that are associated with recovery versus development of chronic symptoms. In this review, we focus on the pathology of neurotransmission after TBI, reflecting on what has been learned from both the preclinical and clinical studies, and we discuss new directions and opportunities for future work.
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http://dx.doi.org/10.1038/s41380-018-0239-6DOI Listing
July 2019

Chronic Dysregulation of Cortical and Subcortical Metabolism After Experimental Traumatic Brain Injury.

Mol Neurobiol 2019 Apr 1;56(4):2908-2921. Epub 2018 Aug 1.

Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45267, USA.

Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. Although chronic disability is common after TBI, effective treatments remain elusive and chronic TBI pathophysiology is not well understood. Early after TBI, brain metabolism is disrupted due to unregulated ion release, mitochondrial damage, and interruption of molecular trafficking. This metabolic disruption causes at least part of the TBI pathology. However, it is not clear how persistent or pervasive metabolic injury is at later stages of injury. Using untargeted H-NMR metabolomics, we examined ex vivo hippocampus, striatum, thalamus, frontal cortex, and brainstem tissue in a rat lateral fluid percussion model of chronic brain injury. We found altered tissue concentrations of metabolites in the hippocampus and thalamus consistent with dysregulation of energy metabolism and excitatory neurotransmission. Furthermore, differential correlation analysis provided additional evidence of metabolic dysregulation, most notably in brainstem and frontal cortex, suggesting that metabolic consequences of injury are persistent and widespread. Interestingly, the patterns of network changes were region-specific. The individual metabolic signatures after injury in different structures of the brain at rest may reflect different compensatory mechanisms engaged to meet variable metabolic demands across brain regions.
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http://dx.doi.org/10.1007/s12035-018-1276-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584385PMC
April 2019

Sex differences in DEK expression in the anterior cingulate cortex and its association with dementia severity in schizophrenia.

Schizophr Res 2018 12 13;202:188-194. Epub 2018 Jul 13.

Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, USA; Department of Psychology Experimental Psychology Graduate Program University of Cincinnati, Cincinnati, OH 45221, USA. Electronic address:

DEK is a chromatin-remodeling phosphoprotein found in most human tissues, but its expression and function in the human brain is largely unknown. DEK depletion in vitro induces cellular and molecular anomalies associated with cognitive impairment, including down-regulation of the canonical Wnt/β-catenin signaling pathway. ToppGene analyses link DEK loss to genes associated with various dementias and age-related cognitive decline. To examine the role of DEK in cognitive impairment in severe mental illness, DEK protein expression was assayed by immunoblot in the anterior cingulate cortex (ACC) of subjects with schizophrenia. Cognitive impairment is a core feature of schizophrenia and cognitive function in subjects was assessed antemortem using the clinical dementia rating (CDR) scale. DEK protein expression was not significantly altered in schizophrenia (n = 20) compared to control subjects (n = 20). Further analysis revealed significant reduction in DEK protein expression in women with schizophrenia, and a significant increase in expression in men with schizophrenia, relative to their same-sex controls. DEK protein expression levels were inversely correlated with dementia severity in women. Conversely, in men, DEK protein expression and dementia severity were positively correlated. Notably, there was no sex difference in DEK protein expression in the control group, suggesting that this sex difference is specific to schizophrenia and not due to inherent differences in DEK expression between males and females. These results suggest a novel, sex-specific role for DEK in cognitive performance and highlight a putative sex-specific link between central nervous system DEK protein expression and a neuropsychiatric disease that is commonly associated with cognitive impairment.
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http://dx.doi.org/10.1016/j.schres.2018.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289789PMC
December 2018

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia.

Mol Psychiatry 2019 09 1;24(9):1319-1328. Epub 2018 Mar 1.

Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.

Schizophrenia is a devastating illness that affects over 2 million people in the United States and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-quantitative polymerase chain reaction was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.
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http://dx.doi.org/10.1038/s41380-018-0035-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119539PMC
September 2019