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

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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 languageEnglish (US)
Article numbere22069
JournalSynapse
Volume73
Issue number1
DOIs
StatePublished - 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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