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.
Highlights
Brain-derived neurotrophic factor (BDNF; mBDNF—mature form of BDNF) promotes the survival of developing peripheral neurons [1,2] and has trophic effects on a variety of neuronal types [3]. mBDNF is highly expressed in many brain regions in response to neuronal activity [4,5] and facilitates activity-dependent synaptic plasticity via tropomyosin-related kinase B (TrkB) receptors [6]
Depressive-like behaviors were not reported for mice overexpressing a nonfunctional TrkB receptor in the forebrain [18,19] or for mice lacking one brain-derived neurotrophic factor (Bdnf) allele (BDNF+/− mice) [18,20,21], these mice were slower to escape in the learned helplessness paradigm of depression [20]
The endogenous Bdnf allele was replaced with a sequence encoding precursor BDNF (proBDNF) containing rare human tandem single nucleotide polymorphism (SNP), at nucleotides 373 (G/T) and 379 (G/T), which change two arginines proximal to the cleavage site to methionine and leucine, respectively, near the cleavage site of proBDNF (Figure 1a, top)
Summary
Brain-derived neurotrophic factor (BDNF; mBDNF—mature form of BDNF) promotes the survival of developing peripheral neurons [1,2] and has trophic effects on a variety of neuronal types [3]. mBDNF is highly expressed in many brain regions in response to neuronal activity [4,5] and facilitates activity-dependent synaptic plasticity via tropomyosin-related kinase B (TrkB) receptors [6]. Male mice with reduced levels of BDNF in forebrain regions exhibit depressive-like behavior [16], and knockdown of BDNF in the dentate gyrus area of the hippocampus in rats produces depressive-like effects [17]. Depressive-like behaviors were not reported for mice overexpressing a nonfunctional TrkB receptor in the forebrain [18,19] or for mice lacking one Bdnf allele (BDNF+/− mice) [18,20,21], these mice were slower to escape in the learned helplessness paradigm of depression [20]. It is indicated that depressive-like behaviors are induced by exposure to stress, which results in reduced levels of mBDNF in the cortex and hippocampus in animal models [22,23,24]. Mishima et al reported that mice deficient for Ca2+-dependent activator protein for secretion 2 (CAPS2), a regulator of dense-core vesicle exocytosis that is involved in the secretion of mBDNF and NT-3, display depressive-like behaviors after chronic treatment with corticosterone [25]
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