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Article ; Online: Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia.

Sahay, Smita / Devine, Emily A / McCullumsmith, Robert E / O'Donovan, Sinead M

2023 Volume 13, Issue 1

Abstract: Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine ... ...

Abstract	Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A
MeSH term(s)	Female ; Humans ; Male ; Dopamine ; Schizophrenia/genetics ; Neurons ; Glutamic Acid ; Adenosine ; RNA, Messenger/genetics
Chemical Substances	Dopamine (VTD58H1Z2X) ; Glutamic Acid (3KX376GY7L) ; Adenosine (K72T3FS567) ; RNA, Messenger
Language	English
Publishing date	2023-12-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13010032
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Article ; Online: Editorial overview: Neuroscience: Advances in the field.

O'Donovan, Sinead M / McCullumsmith, Robert / Shukla, Rammohan

Current opinion in pharmacology

2021 Volume 62, Page(s) 82–84

MeSH term(s)	Humans ; Neurosciences
Language	English
Publishing date	2021-12-20
Publishing country	England
Document type	Editorial
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2021.11.004
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Article ; Online: Strategies to identify candidate repurposable drugs: COVID-19 treatment as a case example.

Imami, Ali S / McCullumsmith, Robert E / O'Donovan, Sinead M

Translational psychiatry

2021 Volume 11, Issue 1, Page(s) 591

Abstract: Drug repurposing is an invaluable strategy to identify new uses for existing drug therapies that overcome many of the time and financial costs associated with novel drug development. The COVID-19 pandemic has driven an unprecedented surge in the ... ...

Abstract	Drug repurposing is an invaluable strategy to identify new uses for existing drug therapies that overcome many of the time and financial costs associated with novel drug development. The COVID-19 pandemic has driven an unprecedented surge in the development and use of bioinformatic tools to identify candidate repurposable drugs. Using COVID-19 as a case study, we discuss examples of machine-learning and signature-based approaches that have been adapted to rapidly identify candidate drugs. The Library of Integrated Network-based Signatures (LINCS) and Connectivity Map (CMap) are commonly used repositories and have the advantage of being amenable to use by scientists with limited bioinformatic training. Next, we discuss how these recent advances in bioinformatic drug repurposing approaches might be adapted to identify repurposable drugs for CNS disorders. As the development of novel therapies that successfully target the cause of neuropsychiatric and neurological disorders has stalled, there is a pressing need for innovative strategies to treat these complex brain disorders. Bioinformatic approaches to identify repurposable drugs provide an exciting avenue of research that offer promise for improved treatments for CNS disorders.
MeSH term(s)	COVID-19/drug therapy ; Humans ; Pandemics ; Pharmaceutical Preparations ; SARS-CoV-2
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2021-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-021-01724-w
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Article: Extracellular Matrix Abnormalities in the Hippocampus of Subjects with Substance Use Disorder.

Valeri, Jake / Stiplosek, Charlotte / O'Donovan, Sinead M / Sinclair, David / Grant, Kathleen / Bollavarapu, Ratna / Platt, Donna M / Stockmeier, Craig A / Gisabella, Barbara / Pantazopoulos, Harry

medRxiv : the preprint server for health sciences

2024

Abstract: Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans ( ... ...

Abstract	Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is currently a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased expression of the ECM protease matrix metalloproteinase 9 (
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.07.23295222
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Article ; Online: Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder.

Valeri, Jake / Stiplosek, Charlotte / O'Donovan, Sinead M / Sinclair, David / Grant, Kathleen A / Bollavarapu, Ratna / Platt, Donna M / Stockmeier, Craig A / Gisabella, Barbara / Pantazopoulos, Harry

Translational psychiatry

2024 Volume 14, Issue 1, Page(s) 115

Abstract	Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is currently a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased expression of the ECM protease matrix metalloproteinase 9 (Mmp9), and increased expression for the excitatory synaptic marker vesicle associated membrane protein 2 (Vamp2). Similar increases in PNNs were observed in monkeys with chronic alcohol self-administration. Subjects with MDD displayed changes opposite to SUD, and subjects with SUD and comorbid MDD had minimal changes in any of the outcome measures examined. Our findings demonstrate that PNNs are increased in SUD, possibly contributing to stabilizing contextual reward memories as suggested by preclinical studies. Our results also point to a previously unsuspected role for CSPG expression in glial cells in SUD. Evidence for increased hippocampal PNNs in SUD suggests that targeting PNNs to weaken contextual reward memories is a promising therapeutic approach for SUD, however comorbidity with MDD is a significant consideration.
MeSH term(s)	Animals ; Humans ; Depressive Disorder, Major/metabolism ; Extracellular Matrix/metabolism ; Neurons/metabolism ; Hippocampus ; Substance-Related Disorders
Language	English
Publishing date	2024-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-024-02833-y
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Article ; Online: Altered purinergic receptor expression in the frontal cortex in schizophrenia.

Alnafisah, Rawan / Lundh, Anna / Asah, Sophie M / Hoeflinger, Julie / Wolfinger, Alyssa / Hamoud, Abdul-Rizaq / McCullumsmith, Robert E / O'Donovan, Sinead M

Schizophrenia (Heidelberg, Germany)

2022 Volume 8, Issue 1, Page(s) 96

Abstract: ATP functions as a neurotransmitter, acting on the ubiquitously expressed family of purinergic P2 receptors. In schizophrenia (SCZ), the pathways that modulate extracellular ATP and its catabolism to adenosine are dysregulated. However, the effects of ... ...

Abstract	ATP functions as a neurotransmitter, acting on the ubiquitously expressed family of purinergic P2 receptors. In schizophrenia (SCZ), the pathways that modulate extracellular ATP and its catabolism to adenosine are dysregulated. However, the effects of altered ATP availability on P2 receptor expression in the brain in SCZ have not been assessed. We assayed P2 receptor mRNA and protein expression in the DLPFC and ACC in subjects diagnosed with SCZ and matched, non-psychiatrically ill controls (n = 20-22/group). P2RX7, P2RX4 and male P2RX5 mRNA expression were significantly increased (p < 0.05) in the DLPFC in SCZ. Expression of P2RX7 protein isoform was also significantly increased (p < 0.05) in the DLPFC in SCZ. Significant increases in P2RX4 and male P2RX5 mRNA expression may be associated with antipsychotic medication effects. We found that P2RX4 and P2RX7 mRNA are significantly correlated with the inflammatory marker SERPINA3, and may suggest an association between upregulated P2XR and neuroinflammation in SCZ. These findings lend support for brain-region dependent dysregulation of the purinergic system in SCZ.
Language	English
Publishing date	2022-11-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	3133210-9
ISSN	2754-6993 ; 2754-6993
ISSN (online)	2754-6993
ISSN	2754-6993
DOI	10.1038/s41537-022-00312-1
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Article: Altered expression of somatostatin signaling molecules and clock genes in the hippocampus of subjects with substance use disorder.

Valeri, Jake / O'Donovan, Sinead M / Wang, Wei / Sinclair, David / Bollavarapu, Ratna / Gisabella, Barbara / Platt, Donna / Stockmeier, Craig / Pantazopoulos, Harry

Frontiers in neuroscience

2022 Volume 16, Page(s) 903941

Abstract: Substance use disorders are a debilitating group of psychiatric disorders with a high degree of comorbidity with major depressive disorder. Sleep and circadian rhythm disturbances are commonly reported in people with substance use disorder and major ... ...

Abstract	Substance use disorders are a debilitating group of psychiatric disorders with a high degree of comorbidity with major depressive disorder. Sleep and circadian rhythm disturbances are commonly reported in people with substance use disorder and major depression and associated with increased risk of relapse. Hippocampal somatostatin signaling is involved in encoding and consolidation of contextual memories which contribute to relapse in substance use disorder. Somatostatin and clock genes also have been implicated in depression, suggesting that these molecules may represent key converging pathways involved in contextual memory processing in substance use and major depression. We used hippocampal tissue from a cohort of subjects with substance use disorder (
Language	English
Publishing date	2022-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2022.903941
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Article: Neuronal alterations in AKT isotype expression in schizophrenia.

Devine, Emily A / Imami, Ali S / Eby, Hunter / Hamoud, Abdul-Rizaq / Golchin, Hasti / Ryan, William / Sahay, Smita / Shedroff, Elizabeth A / Arvay, Taylen / Joyce, Alex W / Asah, Sophie M / Walss-Bass, Consuelo / O'Donovan, Sinead / McCullumsmith, Robert E

Research square

2024

Abstract: Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA ...

Abstract	Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of conical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3940448/v1
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Article ; Online: Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

Hamoud, Abdul-Rizaq / Bach, Karen / Kakrecha, Ojal / Henkel, Nicholas / Wu, Xiaojun / McCullumsmith, Robert E / O'Donovan, Sinead M

International journal of molecular sciences

2022 Volume 23, Issue 19

Abstract: For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in ... ...

Abstract	For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.
MeSH term(s)	Adenosine/metabolism ; Humans ; Incidence ; Neoplasms ; Schizophrenia/drug therapy ; Schizophrenia/metabolism ; Tumor Microenvironment
Chemical Substances	Adenosine (K72T3FS567)
Language	English
Publishing date	2022-10-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms231911835
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Article ; Online: Assessing the effects of antipsychotic medications on schizophrenia functional analysis: a postmortem proteome study.

Alnafisah, Rawan S / Reigle, James / Eladawi, Mahmoud Ali / O'Donovan, Sinead M / Funk, Adam J / Meller, Jaroslaw / Mccullumsmith, Robert E / Shukla, Rammohan

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2022 Volume 47, Issue 12, Page(s) 2033–2041

Abstract: Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding ... ...

Abstract	Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding SCZ pathophysiology, are analyzing the drug effects. We hypothesized that comparing SCZ-altered and APD-influenced signatures derived from the same cohort can provide better insight into SCZ pathophysiology. For this, we performed LCMS-based proteomics on dorsolateral prefrontal cortex (DLPFC) samples from control and SCZ subjects and used statistical approaches to identify SCZ-altered and APD-influenced proteomes, validated experimentally using independent cohorts and published datasets. Functional analysis of both proteomes was contrasted at the biological-pathway, cell-type, subcellular-synaptic, and drug-target levels. In silico validation revealed that the SCZ-altered proteome was conserved across several studies from the DLPFC and other brain areas. At the pathway level, SCZ influenced changes in homeostasis, signal-transduction, cytoskeleton, and dendrites, whereas APD influenced changes in synaptic-signaling, neurotransmitter-regulation, and immune-system processes. At the cell-type level, the SCZ-altered and APD-influenced proteomes were associated with two distinct striatum-projecting layer-5 pyramidal neurons regulating dopaminergic-secretion. At the subcellular synaptic level, compensatory pre- and postsynaptic events were observed. At the drug-target level, dopaminergic processes influenced the SCZ-altered upregulated-proteome, whereas nondopaminergic and a diverse array of non-neuromodulatory mechanisms influenced the downregulated-proteome. Previous findings were not independent of the APD effect and thus require re-evaluation. We identified a hyperdopaminergic cortex and drugs targeting the cognitive SCZ-symptoms and discussed their influence on SCZ pathology in the context of the cortico-striatal pathway.
MeSH term(s)	Antipsychotic Agents/pharmacology ; Antipsychotic Agents/therapeutic use ; Brain/metabolism ; Dopamine/metabolism ; Humans ; Prefrontal Cortex/metabolism ; Proteome/metabolism ; Proteomics ; Schizophrenia/metabolism
Chemical Substances	Antipsychotic Agents ; Proteome ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2022-03-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-022-01310-8
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