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

• Published in: Synapse (New York, N.Y.) Vol. 73; no. 1; pp. e22069 - n/a
• Main Authors: Folsom, Timothy D., Higgins, LeeAnn, Markowski, Todd W., Griffin, Timothy J., Fatemi, S. Hossein
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2019
• Subjects: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - genetics; 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - metabolism; Allosteric properties; Amino acids; Animals; Autism; brain; Endoplasmic reticulum; Excitatory Amino Acid Antagonists - pharmacology; Excitatory amino acid transporter 2; Excitatory Amino Acid Transporter 2 - genetics; Excitatory Amino Acid Transporter 2 - metabolism; Excitatory amino acid transporters; FMR1 protein; FMRP; Forebrain; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; FXS; GAP-43 protein; GAP-43 Protein - genetics; GAP-43 Protein - metabolism; Gene Deletion; Glutamic acid receptors (metabotropic); Intellectual disabilities; Liquid chromatography; Mass spectroscopy; mGluR5; Mice; Mice, Inbred C57BL; MPEP; Neurofilament Proteins - genetics; Neurofilament Proteins - metabolism; Phosphodiesterase; Prosencephalon - drug effects; Prosencephalon - metabolism; Protein expression; Proteins; Proteome - genetics; Proteome - metabolism; Proteomics; Pyridines; Pyridines - pharmacology; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Rab3A protein; Ribonucleoproteins; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Western blotting; FXS; FMRP; MPEP; schizophrenia; brain; mGluR5; autism
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.22069

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. Concordant changes in protein expression in subcellular compartments [total homogenate, synapse, nucleus, and rough endoplasmic reticulum (rER)] via proteomics and western blotting in forebrain neurons of fragile X mental retardation knockout (Fmr1 KO) mice.