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. 2010 Oct 20;1(10):679-690.
doi: 10.1021/cn100032f.

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome

Jenny L Fulks  1 , Bliss E O'Bryhim, Sara K Wenzel, Stephen C Fowler, Elena Vorontsova, Jonathan W Pinkston, Andrea N Ortiz, Michael A Johnson
Affiliations

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome

Jenny L Fulks et al. ACS Chem Neurosci. .

Abstract

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

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Figures

Figure 1
Figure 1
Induction of locomotor activity and focused stereotypy by d-amphetamine sulfate in Fmr1 knockout and WT control mice. Separate groups of mice (n = 6) were used at each dose. Data points are group means, and the brackets indicate ± SEM. The four symbols, asterisk (∗), ampersand (&), pound sign (#), and dollar sign ($), reflect significant differences between means as determined by t tests conducted after initial three-way ANOVA. The ∗ indicates significant differences between wild-type (WT) and Fmr1 knockout mice at the indicated doses. The & designates significant differences between vehicle and each dose of amphetamine for WT mice for a given injection, while # marks differences between vehicle and each amphetamine dose administered to the Fmr1 mice. The $, used in panel D only, designates differences between injection 1 and injection 2 for a given genotype. (A) Distance traveled−Injection 1: (∗) WT vs Fmr1KO at dose 0, t10 = 4.16, p < 0.01; (&) WT 0 vs 1.0 mg/kg, t10 = 4.42, p < 0.01; 0 vs 3.3 mg/kg, t10 = 4.50, p < 0.01; and 0 vs 10.0 mg/kg, t10 = 2.34, p < 0.05 (a decrease); (#) Fmr1 0 vs 1.0 mg/kg, t10 = 3.24, p < 0.01; 0 vs 3.3 mg/kg, t10 = 2.53, p < 0.05; and 0 vs 10.0 mg/kg, t10 = 5.50, p < 0.01. (B) Distance−Injection 2: (∗) WT vs Fmr1 KO at dose 0, t10 = 2.98, p < 0.01; WT vs Fmr1 at dose 3.3 mg/kg, t10 = 6.29, p < 0.001. (&) WT 0 vs 1.0 mg/kg, t10 = 4.12, p < 0.01; 0 vs 3.3 mg/kg, t10 = 7.69, p < 0.01; (#) Fmr1 0 vs 1.0 mg/kg, t10 = 4.25, p < 0.01; 0 vs 3.3, t10 = 3.32, p < 0.01; 0 vs 10.0 mg/kg, t10 = 4.25, p < 0.01 (a decrease). (C) Focused Stereotypy−Injection 1: (∗) WT vs Fmr1 at dose 10.0 mg/kg, t10 = 2.897, p < 0.05. (D) Focused Stereotypy−Injection 2: (∗) WT vs Fmr1 at dose 10.0 mg/kg, t10 = 3.33, p < 0.01; ($) injection 2 vs injection 1, WT, t10 = 2.60, p < 0.05; Fmr1, t10 = 3.04, p < 0.05.
Figure 2
Figure 2
DA release is impaired in 15 week-old Fmr1 KO mice. Representative plots of electrically stimulated DA release obtained in brain slices from a 15 week-old Fmr1 KO mouse and an age-matched WT control mouse. The application of a single, biphasic electrical stimulus pulse (4 ms total duration, 350 μA current) is denoted by the arrow under each plot. Cyclic voltammograms, provided above each plot, confirm the presence of DA.
Figure 3
Figure 3
[DA]p and Vmax are impaired in 15- and 20-week old KO mice compared with aged-matched WT control mice. (A) The open circles represent the experimental data, while the line shows the model fit to the data. (B) When the stimulated DA release of the KO mice were compared with that of the WT mice, a significant difference in the release was seen at 15 and 20 weeks of age. (C) When the data were modeled, Vmax was also determined and the KO were compared with the WT. A significant decrease in Vmax was seen in the 15 and 20 week old mice. Statistics: *p < 0.05, **p < 0.01, ***p < 0.001 (10 weeks, n = 7 WT and 7 KO mice; 15 weeks, n = 6 WT and 6 KO mice; 20 weeks, n = 10 WT and 10 KO mice).
Figure 4
Figure 4
D2 autoreceptor activation and cocaine-induced reserve pool activation were similar in WT and KO mice. (A) Representative data collected in a striatal brain slice from a 20 week old WT mouse. The slice was exposed to cumulatively increasing concentrations of quinpirole while electrically evoked DA release was measured every 5 min. After DA release disappeared, cocaine was added to the slice with the quinpirole to mobilize reserve pool DA. (B) Quinpirole inhibited DA release similarly in WT and KO mice (ANOVA). (C) The percent DA recovery post quinpirole and cocaine showed no difference in the KO and WT mice.
Figure 5
Figure 5
DA uptake is similarly inhibited in the KO and WT striatum. The stimulated release plots (○) were modeled (—) to determine KM for DA uptake during a cumulative treatment regimen. Average values of KM at each AMPH concentration were determined and plotted (inset). There was no significant interaction between genotype and KM or between genotype and AMPH concentration (ANOVA).
Figure 6
Figure 6
AMPH enhances stimulated DA release in brain slices from KO mice but not in those from WT mice. Representative plots of stimulated DA release are shown for WT and KO mice before (—) and after (−−−) treatment with 6 μM AMPH. After AMPH administration, stimulated DA release increased, relative to predrug values, in KO mice but not in WT mice (inset). Statistics: ∗, p < 0.01, t test, n = 4 WT and n = 4 KO mice.
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