Reduction in BDNF from Inefficient Precursor Conversion Influences Nest Building and Promotes Depressive-Like Behavior in Mice

Masami Kojima; Hikari Otabi; Haruko Kumanogoh; Atsushi Toyoda; Masahito Ikawa; Masaru Okabe; Toshiyuki Mizui

doi:10.3390/ijms21113984

Reduction in BDNF from Inefficient Precursor Conversion Influences Nest Building and Promotes Depressive-Like Behavior in Mice

Int J Mol Sci. 2020 Jun 1;21(11):3984. doi: 10.3390/ijms21113984.

Authors

Masami Kojima^{1

2

3}, Hikari Otabi⁴, Haruko Kumanogoh^{1

2}, Atsushi Toyoda⁴, Masahito Ikawa⁵, Masaru Okabe⁵, Toshiyuki Mizui^{1

2}

Affiliations

¹ Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan.
² Core Research for Evolutional Science and Technology (CREST), Kawaguchi 332-0012, Japan.
³ Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan.
⁴ College of Agriculture, Ibaraki University, Ami, Ibaraki 300-0393, Japan.
⁵ Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 5650871, Japan.

Abstract

We generated a knock-in mouse line in which the gene encoding brain-derived neurotrophic factor (Bdnf) was replaced with a sequence for proBDNF containing human single nucleotide polymorphisms encoding arginines proximal to the cleavage site (R125M and R127L). The ratio of the mature form of BDNF (mBDNF) to precursor BDNF (proBDNF) in hippocampal tissue lysates was decreased in a manner dependent on the number of copies of the mutant gene, indicating that the mutations inhibited proteolytic conversion of proBDNF into mBDNF. Although homozygous mice had a proBDNF/mBDNF ratio of ~9:1, they survived until adulthood. The levels of mBDNF were reduced by 57% in heterozygous mutant mice, which exhibited a depressive-like behavior in the tail suspension test and weight gain when housed in social isolation, showing that impaired proBDNF cleavage contributes to stress-induced depressive-like phenotypes. Furthermore, socially isolated heterozygous mice displayed a pronounced deficit in daily nest-building behaviors. These findings suggest that the decreased production of mBDNF by impaired proBDNF cleavage disturbs daily activities in mice.

Keywords: BDNF; SNP; cleavage; depression; nest building; social isolation.

MeSH terms

Alleles
Animals
Behavior, Animal*
Body Weight
Brain-Derived Neurotrophic Factor / metabolism*
Depression / metabolism*
Disease Models, Animal
Female
Gene Knock-In Techniques
Genotype
Heterozygote
Hippocampus / metabolism
Homozygote
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Phenotype
Polymorphism, Single Nucleotide
Risk Factors
Social Isolation

Substances

Brain-Derived Neurotrophic Factor
BDNF protein, human