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. 2012 May;33(5):1001.e7-16.
doi: 10.1016/j.neurobiolaging.2011.03.022. Epub 2011 Apr 30.

Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease

Lifen Zhang  1 , Weidong Le, Wenjie Xie, John A Dani
Affiliations

Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease

Lifen Zhang et al. Neurobiol Aging. 2012 May.

Abstract

The nuclear receptor related 1 (Nurr1) transcription factor contributes to the development and maintenance of dopamine (DA) neurons in the brain. We found that heterozygous Nurr1 knockout (Nurr1 +/-) influenced the age-dependent decline in the number of DA neurons and influenced DA signaling. We examined the DA marker, tyrosine hydroxylase, using immunohistochemistry, and we measured DA signaling using fast-scan cyclic voltammetry in 3 age groups of wild-type (Nurr1 +/+) and mutant (Nurr1 +/-) mice: 3-6, 9-12, and 15-23 mo old. Prior to significant loss of DA neurons and to the onset of parkinsonian symptoms, young Nurr1 +/- mice (3-6 mo) exhibited a decrease in peak evoked DA release that was partially countered by a decrease in the rate of DA reuptake. As peak evoked DA release declined with age for both the wild-type and Nurr1 +/- mice, both genotypes manifested decreased DA reuptake. As the DA release fell further with age, decreased DA reuptake eventually could not adequately compensate the Nurr1 +/- mice. The results indicated that Nurr1 deficiency led to impaired DA release even before significant DA neuron loss.

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Conflict of interest statement

Disclosure Statement

There were no conflicts of interest for this study for any of the authors. The animal procedures were appropriate, and the mice were housed and handled in accordance with the guidelines set forth by the animal care committee at Baylor College of Medicine.

Figures

Fig. 1
Fig. 1
Age-dependent changes in DA neurons and DA content changes in Nurr1 +/− and control (Nurr1 +/+) mice. (A) TH-immunostaining of DA neurons in the substantia nigra (SN) in different age groups. The stereological cell counting of TH-positive cells from Nurr1 +/− mice (black bars) showed a significant decrease compared to age matched control mice (gray bars). (C) Striatal DA content decreased in the dorsal striatal in Nurr1 +/− mice. *p < 0.05 and **p < 0.01 vs age-matched Nurr1 +/+ mice with 5–6 mice in each group.
Fig. 2
Fig. 2
Single-pulse (lp) evoked DA release in Nurr1 +/+ (Ctrl) and Nurr1 +/− (Nurr1) mice (3–6 months) slices from the dorsal striatum. (A) Representative DA signals from controls (Ctrl, gray) and Nurr1 mice (black). The evoked DA signal from Nurr1 mice was smaller in peak amplitude and showed a prolonged decay phase compared to the control. (B) Mean amplitude of the DA signal in Nurr1 mice and the control (n = 30, 38 respectively; ** p < 0.01).
Fig. 3
Fig. 3
Slower decay time of DA signals in Nurr1 +/− mice slices. (A) Comparison of the decay time of the DA signals obtained from the control (Ctrl, gray) and Nurr1 +/− mice (black). The times when the DA signals decay to 90% of the peak (t90) are shown for each representative trace (filled circles). (B) The t90 was significantly longer in Nurr1 +/− mice (black bar) compared to the control (n = 30, 38; ** p < 0.01). (C) Example of normalized DA signals (100% of control amplitude) showing the longer decay time in Nurr1+/− mice (black trace) compared to the control (gray trace). (D) Blocking the DA transporter with GBR (2 μM) abolished the difference in decay of the control and Nurr1 +/− DA signals (shown in C). The peak amplitudes were again normalized to the control’s peak. (E) When DATs were inhibited by GBR, the difference in peak DA amplitude is accentuated between the control (gray) and the Nurr1+/− (black) mice. (F) The average peak DA amplitude was large and significantly different between the two genotypes (n = 10, 15; ** p < 0.01).
Fig. 4
Fig. 4
Age-dependent DA release in Nurr1 +/− and control mice slices. (A) Representative DA signals evoked by single pulse stimulation of slices from mice aged 3 months and 20 months. (B) The mean amplitude of the DA signal for each age group was significantly lower in the Nurr1 +/− mice (black data) compared to the control mice (gray data) (n = 12–38, ** p < 0.01). (C) The decay time (t90) was significantly longer across all age groups in the Nurr1 +/− mice when compared to the 3–6 month control. The decay time for the control mice aged 15–23 months was also significantly increased compared to the 3–6 month control.
Fig. 5
Fig. 5
Frequency dependent DA release in control and Nurr1 +/− mice slices. (A) Representative DA signals evoked by 1-pulse (1p) and 5p trains (at 10 Hz) in the dorsal striatum in the control slices before (Ctrl) and after GBR application (0.2 μM) to control slices (Ctrl GBR, blue traces). (B) Representative DA signals evoked by 1-pulse (1p) and 5p trains (at 10 Hz) in the dorsal striatum in the Nurr1 +/− slices before (Nurr1, orange traces) and after GBR application (0.2 μM) to Nurr1 +/− slices (Nurr1 GBR, teal traces). The Nurr1 +/− and GBR control groups showed greater DA release in response to the 5p stimulation. Scale bars: 3s and 0.5 μM. (C) The DA release evoked by train stimulation (5p at 5–80 Hz) was significantly reduced in the Nurr1 mice compared to the control mice at the age of 3–6 months (n = 30, 31, respectively; ** p < 0.01). In each panel, the left most data points are 1p evoked DA signals, plotted for comparison with the stimulus trains. (D) The area-under-curve for the DA signal evoked by train stimulation was not significantly different between the control and Nurr1 +/− groups. (E) Normalizing the area of the train-evoked DA signal to the 1p evoked DA signal revealed a greater facilitation of DA release in Nurr1 +/− mice (orange data) compared to the control mice (black data). (F) Partial inhibition of the DA transporter using GBR (0.2 μM) on control mice mimicked the release pattern observed in the Nurr1 +/− mice (n = 12, 12; ** p < 0.01).
Fig. 6
Fig. 6
Age-dependent DA signals in control (Nurr1 +/+) mice aged 3–6 months and 15–23 months. (A) The peak amplitude of the DA signal evoked by 1p (left most data points in each panel) or train stimulation (5p at 5–80 Hz) was significantly reduced in the 15–23 month old mice compared to the 3–6 month group (n = 19, 31; * p < 0.05). (B) The area-under-curve of the DA signals from control mice aged 15–23 months was not different from the 3–6 month group. (C) The normalized DA area (train evoked DA signal relative to the 1p evoked DA signal) was increased in the 15–23 month old mice compared to the 3–6 month old mice (* p < 0.05).
Fig. 7
Fig. 7
Differences in frequency-dependent DA release in the Nurr1+/− and control mice slices at 9–12 months and 15–23 months. (A) The DA signal evoked by train stimulation (5p at 5–80 Hz) was significantly decreased in the Nurr1 +/− mice aged 9–12 months compared to the control mice (n = 26, 17; ** p < 0.01). In each panel, the left most data points are 1p evoked DA signals, plotted for comparison with the stimulus trains. (B) The area of the DA signal evoked by train stimulation was not significantly different between the two groups. (C) The peak of the DA signal evoked by train stimulation was significantly decreased in the Nurr1 +/− mice aged 15–23 months compared to comparably aged control mice (n = 27, 19; ** p < 0.01). (D) The area of the DA signal was also reduced in the Nurr1 +/− mice aged 15–23 months compared to comparably aged control mice (n = 27, 19; ** p < 0.01).
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