Salivary Gland Derived BDNF Overexpression in Mice Exerts an Anxiolytic Effect.

Juri Saruta,Ichiro Saito,Masahiro Sugimoto,Yusuke Nakagawa,Keiichi Tsukinoki,Hiroko Inoue,Masahiro To,Tomoko Shimizu,Yuko Yamamoto

doi:10.3390/ijms18091902

Abstract

Brain-derived neurotrophic factor (BDNF) is abundant in the hippocampus and plays critical roles in memory and synapse formation, as well as exerting antidepressant-like effects in psychiatric disorders. We previously reported that BDNF is expressed in salivary glands and affects blood BDNF content. However, the function of salivary BDNF remains unclear. The aim of this study was to generate transgenic mice overexpressing BDNF in the salivary glands. Hence, we used the Lama construct (hemagglutinin (HA)-tagged mouse Bdnf cDNA) to specifically express BDNF in mouse salivary glands. Compared with control mice, Bdnf-HA transgenic mice showed increased blood BDNF and expressed salivary BDNF-HA. Molecular analysis revealed enhanced hippocampal BDNF levels and activation of the BDNF receptor, tyrosine kinase B (TrkB), in transgenic mice. In both the open field and elevated-plus maze tests, transgenic mice showed anxiolytic-like behavioral effects compared with control or sialoadenectomized mice. Among downstream components of the BDNF-TrkB signaling pathway, metabolic activation of the γ-aminobutyric acid (GABA) synthetic pathway was found, including higher levels of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1). Thus, we have established a transgenic mouse expressing BDNF in the parotid gland that may be useful to examine the hippocampal effects of salivary BDNF.

Highlights

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is highly expressed in the hippocampus, and which plays critical roles in memory and synapse formation [1,2]
We constructed TG lines on a C57BL/6 background, in which expression of mouse Bdnf cDNA is regulated by the parotid-specific protein (PSP) promoter (Figure 1A) [25,26]
Of 17 progeny screened by RT-PCR of tail DNA, two (TRM-002 and TRM-014) were positive for the PSP promoter Bdnf -hemagglutinin (HA) transgene

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is highly expressed in the hippocampus, and which plays critical roles in memory and synapse formation [1,2]. Elevating hippocampal BDNF levels attenuates chronic stress in a mouse model of depression [4], while chronic administration of antidepressant drugs increases BDNF expression within the hippocampus [5,6]. Expression of the BDNF receptor, tyrosine kinase B (TrkB), is downregulated in the hippocampus during schizophrenia and mood disorders [9]. Downregulation of hippocampal BDNF-TrkB signaling in schizophrenia and mood disorders is accompanied by changes in glutamate decarboxylase 1 (GAD1) [9], an enzyme involved in production of GABA from glutamate [10]. The link between BDNF-TrkB signaling and GAD1-GABA signaling plays an essential role in improvement of the anxiety state [11]. The functional significance of BDNF in the central nervous system is progressing, the role of BDNF in the periphery remains unclear

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Conclusion