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.
Highlights
Introduction aSynuclein fibrils are the major building blocks of Lewy bodies (LBs) and Lewy neurites, which comprise the neuropathological hallmarks of Parkinson’s disease (PD) and related disorders [1]
Gallyas silver staining did not reveal positive signals (Fig. 8) and ‘‘amyloid’’ a-synucleinopathy could not be detected with thioflavin S staining in the hippocampal formation, even in old (Thy1)-h[A30P]aSYN mice (Fig. S3). These dot-like profiles might be synaptic accumulations of apparently ‘‘normal’’ aSYN. These results demonstrate that the age-dependent cognitive decline of (Thy1)-h[A30P]aSYN transgenic mice is correlated with a parallel impairment in amygdala and hippocampus synaptic plasticity in vivo, as seen by immunohistological analysis of the immediate-early gene product c-Fos and the neuronal activity responsive kinase polo-like kinase 2 (Plk2)
These findings are consistent with previous ex vivo reports about affected synaptic plasticity electrophysiology in hippocampal slices from aged mice expressing transgenic h[A30P]aSYN under control of a mouse prion protein promoter [27] and in corticostriatal slices from different aSYN transgenic mice [28]
Summary
Synuclein (aSYN) fibrils are the major building blocks of Lewy bodies (LBs) and Lewy neurites, which comprise the neuropathological hallmarks of Parkinson’s disease (PD) and related disorders [1]. There are synaptic aSYN accumulations in the hippocampal formation of human asynucleinopathy patients and a-synuclein transgenic mouse models [4,5]. Several aSYN transgenic mouse models have been developed in the past [10], and cognitive impairments in such mouse models are emerging [4,11,12]. Cognitive deficits have been correlated with aSYN neuropathology in the amygdala and hippocampus. It remains largely unknown if and how asynucleinpathy affects neurotransmission and synaptic plasticity in vivo
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