title: Impaired c-Fos and polo-like kinase 2 induction in the limbic system of fear-conditioned α-synuclein transgenic mice.
abstract: α-Synuclein (αSYN) is genetically and neuropathologically linked to a spectrum of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, and related disorders. Cognitive impairment is recapitulated in several αSYN transgenic mouse lines. However, the mechanisms of dysfunction in affected neurons are largely unknown. Here we measured neuronal activity induced gene products in the limbic system of αSYN transgenic mice upon fear conditioning (FC). Induction of the synaptic plasticity marker c-Fos was significantly reduced in the amygdala and hippocampus of (Thy1)-h[A30P]αSYN transgenic mice in an age-dependent manner. Similarly, the neuronal activity inducible polo-like kinase 2 (Plk2) that can phosphorylate αSYN at the pathological site serine-129 was up-regulated in both brain regions upon FC. Plk2 inductions were also significantly impaired in aged (Thy1)-h[A30P]αSYN transgenic mice, both in the amygdala and hippocampus. Plk2 inductions in the amygdala after FC were paralleled by a small but significant increase in the number of neuronal cell bodies immunopositive for serine-129 phosphorylated αSYN in young but not aged (Thy1)-h[A30P]αSYN transgenic mice. In addition, we observed in the aged hippocampus a distinct type of apparently unmodified transgenic αSYN profiles resembling synaptic accumulations of αSYN. Thus, the cognitive decline observed in aged αSYN transgenic mice might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct αSYN species.
authors.affiliation: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schell
authors.forename: Cindy
authors.initials: C
authors.lastname: Boden
authors.forename: André Maia
authors.initials: AM
authors.lastname: Chagas
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D003072:Cognition Disorders; D015331:Cohort Studies; D003214:Conditioning, Classical; D005239:Fear; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008032:Limbic System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016622:Silver Staining / Q000379:methods; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission; D013997:Time Factors; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; C444640:serum-inducible kinase