Preliminary Study On BDNF-GABAergic Dysfunction In Late-life Anxiety

Objedtive: In recent years, the incidence of late-life anxiety is growing up, which has become a serious threat to the health of elderly. γ-aminobutyric acid(GABA)ergic plays a key role in regulating mood and its dysfunction can induce anxiety. Brain-derived neurotrophic factor(BDNF) is not only involved in the regulation of GABAergic function but also improvement of the anxiety-related behavior. BDNF is reducing along with aging. Therefore, we hypothesis that the deficit of BDNF in aging brain can induce GABAergic dysfunction which contributes to late-life anxiety, and those pseudo-BDNF components may exert anxiolytic effect by restoring the GABAergic plasticity. This study is designed to explore the relationship of BDNF-GABA-anxiety in aging mice and the potential anxiolytic effect of BDNF for late-life anxiety.Methods: 1. BDNF knockdown-GABAergic dysfunction-anxiety associativity analysisMale mice were randomly divided into three groups: 3 month negative control(3 Mon), 12 month negative control group(12Mon) and 12 month mice undergo BDNF knockdown(12Mon/KD). The BDNF was knocked down in gyrus dentatus by injection of BDNF-LVsh RNA, after 21 days of injection, the elevated plus-maze(EPM) test was used to study the degree of anxiety behavior in mice, and Enzyme Linked Immunosorbent Assay(ELISA) was used to measure GABA and BDNF level in hippocampus and cortex.2. Exogenous BDNF anti-anxiety effect on aging mice and the GABAergic plasticity-related mechanismMale mice were randomly divided into four groups: 3 month control(3Mon), 12 month control(12 Mon), 12 month BDNF group(12 Mon/BDNF), 12 month fluoxetine group(12 Mon/FXT). The exogenous BDNF were given by intraperitional injection for 21 days, then the EPM test was used to study the degree of anxiety behavior and the ELISA was used to measure GABA and BDNF level in hippocampus and cortex; GABAA-R subunits α1, α2 and α5 expression in hippocampus and cortex were detected by western blot.Result: 1. BDNF knockdown-GABAergic dysfunction-anxiety associativity analysis1.1 In EPM text, compared to 3Mon group, 12Mon/KD and 12 Mon group has a decreasing trend of OE%; compared to 12 Mon group, 12Mon/KD group has a reducing trend of OT%.1.2 Compared to 3Mon group, BDNF levels in cortex of 12Mon/KD groupwere decreased significantly(P<0.05); BDNF levels in hippocampus of 12Mon/KD and 12 Mon group were decreased significantly(P<0.001, P<0.01). 1.3 Both the GABA and BDNF levels has positive correlative property with OT% and OE%(P<0.05) in hippocampus and cortex of mice.2. Exogenous BDNF anti-anxiety effect on aging mice and the GABAergic plasticity-related mechanism2.1 In EPM test, compared to 12 Mon group, 12Mon/BDNF and 12Mon/FXT increased OT% and OE% significantly(P<0.05; P<0.01). Compared to 12 Mon group, OE% of 3Mon group increased significanty(P<0.01).In step-down test, of, compared to 12 Mon group, for learning capacity test, the latence 12Mon/BDNF group were increased significantly(P<0.05); In memory capacity test, the number of errors were reduced and incubation period were increased significantly in 12Mon/BDNF group.2.2 Compared to 12 Mon, both the BDNF and GABA level were increased significantly(P<0.05, P<0.001 respectively) in hippocampus of 12Mon/FXT and 12Mon/BDNF group.2.3 Compared to 12 Mon, both the GABAA-R α2 and GABAA-R α5 were increased significantly(P<0.05; P<0.01 respectively) in hippocampus of 12Mon/BDNF group.2.4 There is a positive correlation between GABA levels and OT% in hippocampus and cortex, and a positive correlation between BDNF levels and OE% in hippocampus. There is also a positive correlation between GABA and BDNF levels inhippocampus; GABAA-R α1, GABAA-R α2 and GABAA-R α5 also has positive correlation with BDNF levels in hippocampus. GABAA-R α2 and GABAA-R α5 has positive correlation with BDNF levels in cortex.Conclusion: 1. The deficit of BDNF can increase anxiety susceptibility in aging mice, the mechanism is related to the GABAergic dysfunction.2. Exogenous BDNF can reduce anxiety behavior and improve memory and learning function in aging mice by restoring GABAergic function.3. BDNF might be a potential target for late-life nxiety.