title: Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats.
abstract: An increasing number of studies have revealed associations between pre- and perinatal immune activation and the development of schizophrenia and autism spectrum disorders (ASDs). Accordingly, neuroimmune crosstalk has a considerably large impact on brain development during early ontogenesis. While a plethora of heterogeneous abnormalities have already been described in established maternal immune activation (MIA) rodent and primate animal models, which highly correlate to those found in human diseases, the underlying molecular background remains obscure. In the current study, we describe the long-term effects of MIA on the neocortical pre- and postsynaptic proteome of adolescent rat offspring in detail. Molecular differences were revealed in sub-synaptic fractions, which were first thoroughly characterized using independent methods. The widespread proteomic examination of cortical samples from offspring exposed to maternal lipopolysaccharide administration at embryonic day 13.5 was conducted via combinations of different gel-based proteomic techniques and tandem mass spectrometry. Our experimentally validated proteomic data revealed more pre- than postsynaptic protein level changes in the offspring. The results propose the relevance of altered synaptic vesicle recycling, cytoskeletal structure and energy metabolism in the presynaptic region in addition to alterations in vesicle trafficking, the cytoskeleton and signal transduction in the postsynaptic compartment in MIA offspring. Differing levels of the prominent signaling regulator molecule calcium/calmodulin-dependent protein kinase II in the postsynapse was validated and identified specifically in the prefrontal cortex. Finally, several potential common molecular regulators of these altered proteins, which are already known to be implicated in schizophrenia and ASD, were identified and assessed. In summary, unexpectedly widespread changes in the synaptic molecular machinery in MIA rats were demonstrated which might underlie the pathological cortical functions that are characteristic of schizophrenia and ASD.
authors.affiliation: Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary; MTA-ELTE NAP B Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Balázs A
authors.initials: BA
authors.lastname: Györffy
authors.affiliation: MTA-TTK NAP B MS Neuroproteomics Group, Hungarian Academy of Sciences, Budapest H-1117, Hungary; Department of Pediatrics, Medical University of Vienna, Vienna A-1090, Austria.
authors.forename: Péter
authors.initials: P
authors.lastname: Gulyássy
authors.affiliation: Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary; MTA-ELTE NAP B Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gellén
authors.affiliation: Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary; MTA-ELTE NAP B Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Völgyi
authors.affiliation: Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Madarasi
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Viktor
authors.initials: V
authors.lastname: Kis
authors.affiliation: MTA-TTK NAP B MS Neuroproteomics Group, Hungarian Academy of Sciences, Budapest H-1117, Hungary.
authors.forename: Olivér
authors.initials: O
authors.lastname: Ozohanics
authors.affiliation: CRU Hungary Kft., Miskolc H-3529, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Papp
authors.affiliation: CRU Hungary Kft., Miskolc H-3529, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Kovács
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna A-1090, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
authors.affiliation: MTA-ELTE NAP B Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Dobolyi
authors.affiliation: MTA-ELTE NAP B Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Kardos
authors.affiliation: MTA-TTK NAP B MS Neuroproteomics Group, Hungarian Academy of Sciences, Budapest H-1117, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Drahos
authors.affiliation: Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary; MTA-TTK NAP B MS Neuroproteomics Group, Hungarian Academy of Sciences, Budapest H-1117, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
authors.affiliation: Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary; Department of Physiology and Neurobiology, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary. Electronic address: kakekesi@ttk.elte.hu.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Kékesi
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology* / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000209:etiology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D013574:Synaptosomes / Q000378:metabolism* / Q000473:pathology
chemical_list: D008070:Lipopolysaccharides; D020543:Proteome
keywords: Autism spectrum disorder (ASD); Cerebral cortex; Maternal immune activation (MIA); Neuroproteomics; Schizophrenia; Synaptosome