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

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 ?-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.

SUBMITTER: Saruta J

PROVIDER: S-EPMC5618551 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Saruta Juri J To Masahiro M Sugimoto Masahiro M Yamamoto Yuko Y Shimizu Tomoko T Nakagawa Yusuke Y Inoue Hiroko H Saito Ichiro I Tsukinoki Keiichi K

International journal of molecular sciences 20170905 9

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 (hemaggluti ...[more]

PMID: 28872625

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Project description:BackgroundChronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders.MethodsThe chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala2-GIP) and antagonist (Pro3-GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR.ResultsIn the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala2-GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro3-GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice.ConclusionsGIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.

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

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

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