Reduction of BDNF results in GABAergic neuroplasticity dysfunction and contributes to late-life anxiety disorder.

Abstract

The GABAergic neuroplasticity dysfunction (GND) has been proposed as a distinct pathology for late-life anxiety disorder (LLAD). Brain-derived neurotrophic factor (BDNF) is a critical signaling molecule that regulates the GABAergic neuroplasticity. This research was designed to explore our hypothesis that the reduction of BDNF along with aging could induce GND, which might contribute to LLAD, and application of exogenous BDNF might reverse LLAD by restoring the GABAergic neuroplasticity. We focused on the hippocampus because it is the neural core of mood regulation and can be affected by aging. Compared to young mice, BDNF messenger RNA (mRNA) and protein levels and those core neuroplasticity factors (neurotransmitter γ-aminobutyric acid [GABA] level, GABAA-R α2 and α5 subunits expression and GABA+ neurons) in hippocampus markedly decreased with anxiety-like behavior in aged mice. Knocking down BDNF mRNA in aged mice resulted in further dysfunction of GABAergic neuroplasticity and higher anxiety phenotype. Inversely, chronic exogenous BDNF treatment attenuated anxiety-like behavior, improved the cognitive function, and increased the neuroplasticity factors. We demonstrated that the basic function of BDNF in hippocampus was negatively correlated with GND and anxiety-like behavior of aged mice. These results provided evidence of a causal relationship between the reduced BDNF function in hippocampus and the anxiety susceptibility of aged mice. Gene knockdown mice model indicates the mechanism of low BDNF function in LLAD, particularly affecting GABA neurons, therefore bridging the neurotrophic factor and GABAergic neuroplasticity hypotheses of LLAD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).