Impaired c-Fos and Polo-Like Kinase 2 Induction in the Limbic System of Fear-conditioned α-Synuclein Transgenic Mice

alpha-Synuclein (alpha SYN) 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 alpha SYN 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 alpha SYN 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]alpha SYN transgenic mice in an age-dependent manner. Similarly, the neuronal activity inducible polo-like kinase 2 (Plk2) that can phosphorylate alpha SYN 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] alpha SYN 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 alpha SYN in young but not aged (Thy1)-h[A30P] alpha SYN transgenic mice. In addition, we observed in the aged hippocampus a distinct type of apparently unmodified transgenic alpha SYN profiles resembling synaptic accumulations of alpha SYN. Thus, the cognitive decline observed in aged alpha SYN transgenic mice might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct alpha SYN species.