Aberrant striatal dopamine transmitter dynamics in brain-derived neurotrophic factor-deficient mice

Abstract

Brain-derived neurotrophic factor (BDNF) modulates the synaptic transmission of several monoaminergic neuronal systems, including forebrain dopamine-containing neurons. Recent evidence shows a strong correlation between neuropsychiatric disorders and BDNF hypofunction. The aim of the present study was to characterize the effect of low endogenous levels of BDNF on dopamine system function in the caudate-putamen using heterozygous BDNF (BDNF(+/-) ) mice. Apparent extracellular dopamine levels in the caudate-putamen, determined by quantitative microdialysis, were significantly elevated in BDNF(+/-) mice compared with wildtype controls (12 vs. 5 nM, respectively). BDNF(+/-) mice also had a potentiated increase in dopamine levels following potassium (120 mM)-stimulation (10-fold) relative to wildtype controls (6-fold). Slice fast-scan cyclic voltammetry revealed that BDNF(+/-) mice had reductions in both electrically evoked dopamine release and dopamine uptake rates in the caudate-putamen. Superfusion of BDNF led to partial recovery of the electrically stimulated dopamine release response in BDNF(+/-) mice. Conversely, tissue accumulation of L-3,4-dihydroxyphenylalanine, extracellular levels of dopamine metabolites, and spontaneous locomotor activity were unaltered. Together, this study indicates that endogenous BDNF influences dopamine system homeostasis by regulating the release and uptake dynamics of pre-synaptic dopamine transmission.

Figure 1

Linear regression analysis of dopamine (DA) levels in the CPu of wildtype (WT) and BDNF^+/− mice determined by zero net flux. The x-intercept (point of zero net flux) represents an estimate of basal extracellular DA levels (DA_ext). Inset shows the mean ± SEM of apparent DA_ext (n = 6/group). ***p < 0.001 compared to WT mice (Student’s t-test).

Figure 2

Potassium-evoked dopamine (DA) response in the CPu of wildtype (WT) and BDNF^+/− mice. (a) Time-course of extracellular dopamine elevations following 20 min perfusion of moderate (60 mM K⁺, dashed line) to high (120 mM K⁺, solid line) potassium aCSF. Data represent mean baseline-corrected dialysate dopamine levels ± SEM (n = 6/group). ^&p < 0.05, compared to WT 60 mM K⁺ group; ^###p < 0.001, compared to BDNF^+/− 60 mM K⁺ group; **p < 0.01, ***p < 0.001, compared to WT 120 mM K⁺ group (two-way ANOVA). Inset shows the combined baseline values (uncorrected for probe recovery, mean ± SEM) for WT and BDNF^+/− mice from both K⁺ treatment groups. (b) Area under the curve (AUC) of the cumulative increase in extracellular DA over four 20 min samples (80 - 140 min) following K⁺ perfusion. Data are mean AUC ± SEM. ^###p < 0.01 compared to BDNF^+/− 60 mM K⁺ group; **p < 0.05 compared to WT 120 mM K⁺ group (Student’s t-test).

Figure 3

FSCV measurements following single-pulse stimulation in dorsal CPu slices from wildtype (WT) and BDNF^+/− mice. Mean ± SEM of (a) maximum electrically-evoked DA release and (b) DA uptake rates measured from untreated mice (n = 22-24/group). Representative concentration versus time traces and corresponding cyclic voltammograms (inset) are shown for (c) WT and (d) BDNF ^+/− mice (n = 5/group) prior to (pre-BDNF baseline, solid black line) and following 30 min perfusion with BDNF (100 ng/ml, dashed gray line). The effect of exogenous BDNF application on (e) DA release (normalized to % of WT baseline) and (f) DA uptake rates are shown as means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared to WT (baseline or pre-BDNF); ^###p < 0.001 compared to BDNF^+/− pre-BDNF (Student’s t-test).

Figure 4

Dopamine synthesis and metabolism in the CPu of wildtype (WT) and BDNF^+/− mice. (a) L-DOPA tissue accumulation following treatment with NSD-1015 and GBL. Data are means ± SEM and expressed as ng L-DOPA/mg wet weight of tissue (ww) (n = 11-13/group). (b) Extracellular levels of the dopamine metabolites, DOPAC and HVA as measured by microdialysis. Data are means ± SEM of uncorrected baseline values (n = 10-16/group).

Figure 5

Home cage locomotor activity measured in BDNF^+/− and wildtype (WT) mice as distance traveled (cm) with respect to time. Data are means ± SEM (n = 7-8/group). Inset shows the total distance traveled over 120 min for each genotype.