Overexpression of Cerebral Dopamine Neurotrophic Factor (CDNF) in the Hippocampus Enhances Social Interest in C57BL/6J Mice

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Abstract

Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent in the context of Parkinson’s disease (PD). There is evidence that the neuroprotective properties of CDNF are associated with its regulatory effect on the unfolded protein response (UPR). Behavioral and psychological symptoms are an integral part of PD and other neurodegenerative diseases. However, information on the effect of CDNF on non-motor behavior is very scarce. Therefore, the aim of this study was to investigate the effect of CDNF overexpression in the hippocampus on exploratory, social, anxiety-like, depressive-like behavior and spatial learning, as well as on the expression of UPR genes in C57Bl/6J mice. Four weeks after stereotaxic injection of the adeno-associated viral vector AAV-CDNF, which overexpresses CDNF in the dorsal hippocampus, we found an increase in social interest in the three-chamber social test and the number and duration of social contacts in the resident-intruder test in the CDNF overexpression group. However, CDNF overexpression had no effect on UPR gene expression.

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About the authors

D. V. Eremin

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

Ya. P. Kaminskaya

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

T. V. Ilchibaeva

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

V. S. Naumenko

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

A. S. Tsybko

Institute of Cytology and Genetics, Siberian Branch of RAS

Author for correspondence.
Email: antoncybko@mail.ru
Russian Federation, Novosibirsk

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2. Fig. 1. The order of behavioral tests after the introduction of an adeno-associated viral construct providing overexpression of CDNF in the hippocampus.

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3. Fig. 2. Cdnf mRNA level (a), CDNF protein level (b), and immunohistochemical staining of hippocampal sections (c) with antibodies to CDNF and calreticulin in mice injected with AAV_CDNF or AAV_EGFP. Protein levels are presented in relative units normalized to the corresponding GAPDH protein level. mRNA level is presented as the number of gene copies per 100 copies of the Polr2a gene. *** p < 0.001 compared to the control group.

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4. Fig. 3. Effect of CDNF overexpression in the hippocampus on neophobia in the novel object recognition test (a), social preference index in the three-chamber social test (b), number (c) and duration (d) of sniffs, number (e) and duration (e) of attacks in the resident-intruder test (d). *p < 0.05 compared to the control group.

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5. Fig. 4. Effect of hippocampal CDNF overexpression on spatial learning in the Morris water maze. Distance to platform (a); distance traveled (b), *** p < 0.001 compared to day 1 for AAV_EGFP, ### p < 0.001 compared to day 1 for AAV_CDNF; time spent on platform (c), *** p < 0.001 compared to day 1 for AAV_EGF, ### p < 0.001 compared to day 1 for AAV_CDNF; time spent in target sector on day 5 (d) *** p < 0.001 compared to opposite sector, ### p < 0.001 compared to 25% (random sector).

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6. Fig. 5. Effect of CDNF overexpression in the hippocampus on the mRNA levels of Fos (a), Creb (e), c-Fos (b), CREB (e) proteins, their phosphorylated forms (c, g) and their ratio (d, h). Protein levels are presented in relative units normalized to the corresponding GAPDH protein level. The mRNA level is presented as the number of gene copies per 100 copies of the Polr2a gene.

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7. Fig. 6. Effect of CDNF overexpression in the hippocampus on the mRNA levels of the genes Hspa5 (encodes the protein GRP78) (a), Eif2ak3 (encodes the protein PERK) (b), Atf6 (c), and Ern1 (encodes the protein IRE1) (d), as well as the ratio of the mRNA level of the spliced ​​form of the gene Xbp1 to the unspliced ​​form (e). The mRNA level is presented as the number of gene copies per 100 copies of the gene Polr2a.

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