Research report
α-Synuclein knockout mice have cognitive impairments

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Abstract

α-Synuclein is a member of the synuclein family of cytoplasmic, predominantly neuron-specific proteins. Considerable amount of α-synuclein is found in axons and presynaptic terminals of neurons located in brain areas responsible for emotions and memory. In the present study we have carried out behavioral evaluation of spatial and working long-term memory of α-synuclein knockout mice. Our data shows that α-synuclein knockout mice have reduced learning ability in tests requiring both working and spatial memory. For the first time we have demonstrated that α-synuclein is necessary for these types of learning.

Highlights

► We investigated the role of α-synuclein in learning which involves both working and spatial memory. ► Mice that lack α-synuclein gene demonstrate impairments of working memory and spatial learning. ► Target inactivation of α-synuclein gene simulates some aspects of pathogenesis of α-synucleinopathy.

Introduction

Alpha(α)-synuclein belongs to synuclein family, which consists of three members: α-, β- and γ-synuclein. Synucleins are predominantly neuronal proteins localized in presynaptic terminals with molecular weight of about 14–20 kDa and are characteristic of only vertebrates. α-Synuclein is shown to be involved in pathogenesis of several neurodegenerative disorders, namely, the synucleinopathies [24]. Aggregated forms of α-synuclein represent the main component of Lewy bodies in Parkinson's disease and dementia with Lewy bodies. Such diseases can be accompanied by cognitive impairments [1], [7].

Functions of α-synuclein are still not fully understood. Its involvement in synaptic regulation and neuroplasticity [28], [36], cytoprotection [36], chaperone activity [38] is considered to have been proved. In particular, α-synuclein participates in the regulation of monoamine neurotransmission and recirculation of synaptic vesicles [10], [29].

α-Synuclein is highly expressed in hippocampus, the structure directly involved in spatial learning [23]. Also, the expression of synelfin gene (an α-synuclein ortholog) in anatomical structures of brain involved in songbird learning was shown in zebra finch [42].

Taking into account indirect evidence, in 1999 Clayton and George suggested possible participation of α-synuclein in learning and memory functioning [12]. At the same time, some authors demonstrated that young mice lacking α-synuclein gene did not show any impairments of spatial learning [9], but the results of this study are not conclusive. Thus, the role of α-synuclein in formation of various types of memory has not been studied enough and the results of the studies are questionable.

In the present study we address the role of α-synuclein in learning which involves both working and spatial memory. We demonstrate that old mice with targeted inactivation of α-synuclein gene show impairment of this type of learning.

Section snippets

Animals

Transgenic mice on C57BL/6J genetic background were obtained from Cardiff University Transgenic Animal Unit and characterized previously [2]. Control animals with no genome modifications (WT), and mice with targeted null mutation of the gene encoding α-synuclein (α-KO), descended from the common heterozygous ancestors. Mouse genotyping was carried out as described previously [32]. WT and α-KO cohorts were housed individually in the same conditions on a 12 h light/dark cycle. Mice had free access

Rod suspension test

Two experimental groups of 10-month animals were used in the test: WT (n = 14) and α-KO (n = 12). The results of observations are presented in Fig. 1A. During the test the α-KO group did not show reliable differences from WT mice.

Open field test

Two experimental groups of 10-month animals were used in the test: WT (n = 14) and α-KO (n = 12). The results of observations are presented in Fig. 1B. The decrease in the whole distance overcome and average movement velocity by 23% (U = 32.5, p = 0.023) and 24% (U = 31.5, p = 0.02)

Discussion

On the first stage of the work locomotor abilities of experimental animals were estimated. The α-KO mice showed a slightly decreased motion activity. However, at the same time statistically significant difference in force and stamina was not shown. Moreover, on average the rates were even better. Previous research had not revealed any locomotor disorders in the α-KO group as well [2], [34]. The smaller distance overcome and movement speed seem to result from the poorly expressed response to

Conflicts of interest statement

The authors declare no actual or potential conflicts of interest.

Acknowledgments

We would like to thank the student of National Research University ‘Higher School of Economics’ Anastasia Rogacheva for helping to translate the article.

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