Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2-Methyl-6-(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia

Timothy D. Folsom; LeeAnn Higgins; Todd W. Markowski; Timothy J Griffin; S H Fatemi

doi:10.1002/syn.22069

Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2-Methyl-6-(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia

Timothy D. Folsom, LeeAnn Higgins, Todd W. Markowski, Timothy J Griffin, S H Fatemi

Research output: Contribution to journal › Article › peer-review

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Abstract

The fragile X mental retardation 1 knockout (Fmr1 KO) mouse replicates behavioral deficits associated with autism, fragile X syndrome, and schizophrenia. Less is known whether protein expression changes are consistent with findings in subjects with schizophrenia. In the current study, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics to determine the protein expression of four subcellular fractions in the forebrains of Fmr1 KO mice vs. C57BL/6 J mice and the effect of a negative allosteric modulator of mGluR5—2-Methyl-6-(phenylethynyl)pyridine (MPEP)—on protein expression. Strain- and treatment-specific differential expression of proteins was observed, many of which have previously been observed in the brains of subjects with schizophrenia. Western blotting verified the direction and magnitude of change for several proteins in different subcellular fractions as follows: neurofilament light protein (NEFL) and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP) in the total homogenate; heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC) and heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) in the nuclear fraction; excitatory amino acid transporter 2 (EAAT2) and ras-related protein rab 3a (RAB3A) in the synaptic fraction; and ras-related protein rab 35 (RAB35) and neuromodulin (GAP43) in the rough endoplasmic reticulum fraction. Individuals with FXS do not display symptoms of schizophrenia. However, the biomarkers that have been identified suggest that the Fmr1 KO model could potentially be useful in the study of schizophrenia.

Original language	English (US)
Article number	e22069
Journal	Synapse
Volume	73
Issue number	1
DOIs	https://doi.org/10.1002/syn.22069
State	Published - Jan 2019

Bibliographical note

Funding Information:
This work is supported by the Winston and Maxine Wallin Neuroscience Discovery Fund to S.H. Fatemi who is also supported by the Bernstein Endowed Chair in Adult Psychiatry and the Ewald Bipolar Disease Research Fund. Technical advice on subcellular fractionation technique from Dr. J.H. Meador‐Woodruff, Dr. T.M. Mueller, and Mr. M.S. Simmons is gratefully acknowledged. The authors recognize the Center for Mass Spectrometry and Proteomics at the University of Minnesota and various supporting agencies, including the National Science Foundation for Major Research Instrumentation grants 9871237 and NSF‐DBI‐0215759 used to purchase the instruments described in this study (TJG). Supporting agencies are listed: https://www.cbs.umn.edu/msp/about. The authors declare that there is no conflict of interest.

Funding Information:
Winston and Maxine Wallin Neuroscience Discovery Fund, Grant/Award Number: N/A; University of Minnesota; National Science Foundation, Grant/Award Number: 9871237

Publisher Copyright:
© 2018 Wiley Periodicals, Inc.

Keywords

FMRP
FXS
MPEP
autism
brain
mGluR5
schizophrenia

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Folsom, T. D., Higgins, L., Markowski, T. W., Griffin, T. J., & Fatemi, S. H. (2019). Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2-Methyl-6-(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia. Synapse, 73(1), Article e22069. https://doi.org/10.1002/syn.22069

Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2-Methyl-6-(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia. / Folsom, Timothy D.; Higgins, LeeAnn ; Markowski, Todd W. et al.
In: Synapse, Vol. 73, No. 1, e22069, 01.2019.

Research output: Contribution to journal › Article › peer-review

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title = "Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2-Methyl-6-(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia",

abstract = "The fragile X mental retardation 1 knockout (Fmr1 KO) mouse replicates behavioral deficits associated with autism, fragile X syndrome, and schizophrenia. Less is known whether protein expression changes are consistent with findings in subjects with schizophrenia. In the current study, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics to determine the protein expression of four subcellular fractions in the forebrains of Fmr1 KO mice vs. C57BL/6 J mice and the effect of a negative allosteric modulator of mGluR5—2-Methyl-6-(phenylethynyl)pyridine (MPEP)—on protein expression. Strain- and treatment-specific differential expression of proteins was observed, many of which have previously been observed in the brains of subjects with schizophrenia. Western blotting verified the direction and magnitude of change for several proteins in different subcellular fractions as follows: neurofilament light protein (NEFL) and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP) in the total homogenate; heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC) and heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) in the nuclear fraction; excitatory amino acid transporter 2 (EAAT2) and ras-related protein rab 3a (RAB3A) in the synaptic fraction; and ras-related protein rab 35 (RAB35) and neuromodulin (GAP43) in the rough endoplasmic reticulum fraction. Individuals with FXS do not display symptoms of schizophrenia. However, the biomarkers that have been identified suggest that the Fmr1 KO model could potentially be useful in the study of schizophrenia.",

keywords = "FMRP, FXS, MPEP, autism, brain, mGluR5, schizophrenia",

author = "Folsom, {Timothy D.} and LeeAnn Higgins and Markowski, {Todd W.} and Griffin, {Timothy J} and Fatemi, {S H}",

note = "Funding Information: This work is supported by the Winston and Maxine Wallin Neuroscience Discovery Fund to S.H. Fatemi who is also supported by the Bernstein Endowed Chair in Adult Psychiatry and the Ewald Bipolar Disease Research Fund. Technical advice on subcellular fractionation technique from Dr. J.H. Meador‐Woodruff, Dr. T.M. Mueller, and Mr. M.S. Simmons is gratefully acknowledged. The authors recognize the Center for Mass Spectrometry and Proteomics at the University of Minnesota and various supporting agencies, including the National Science Foundation for Major Research Instrumentation grants 9871237 and NSF‐DBI‐0215759 used to purchase the instruments described in this study (TJG). Supporting agencies are listed: https://www.cbs.umn.edu/msp/about. The authors declare that there is no conflict of interest. Funding Information: Winston and Maxine Wallin Neuroscience Discovery Fund, Grant/Award Number: N/A; University of Minnesota; National Science Foundation, Grant/Award Number: 9871237 Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",

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Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2-Methyl-6-(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia

Abstract

Bibliographical note

Keywords

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