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Keywords:

  • Dopamine;
  • Hypoxanthine-guanine phosphoribosyltransferase;
  • Lesch-Nyhan disease;
  • Basal ganglia;
  • Striatum;
  • Knockout

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. TH, AADC, and ChAT activity in three mouse strains
  6. DISCUSSION
  7. Acknowledgements

Abstract : Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit a characteristic pattern of neurological and behavioral features attributable in part to dysfunction of basal ganglia dopamine systems. In the current studies, striatal dopamine loss was investigated in five different HPRT-deficient strains of mice carrying one of two different HPRT gene mutations. Caudoputamen dopamine concentrations were significantly reduced in all five of the strains, with deficits ranging from 50.7 to 61.1%. Mesolimbic dopamine was significantly reduced in only three of the five strains, with a range of 31.6-38.6%. The reduction of caudoputamen dopamine was age dependent, emerging between 4 and 12 weeks of age. Tyrosine hydroxylase and aromatic amino acid decarboxylase, two enzymes responsible for the synthesis of dopamine, were reduced by 22.4-37.3 and 22.2-43.1%, respectively. These results demonstrate that HPRT deficiency is strongly associated with a loss of basal ganglia dopamine. The magnitude of dopamine loss measurable is dependent on the genetic background of the mouse strain used, the basal ganglia sub-region examined, and the age of the animals at assessment.

Lesch-Nyhan disease (LND) is a developmental disorder associated with a characteristic neurobehavioral syndrome that includes dystonia, chorea, dysarthria, spasticity, varying degrees of cognitive disability, and aggressive and self-injurious behaviors (Sege-Peterson et al., 1992b ; Rossiter and Caskey, 1995). A deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT ; EC 2.4.2.8) has been identified as the cause of the disease, and many different mutations of the HPRT gene from affected patients have been characterized (Davidson et al., 1991 ; Sege-Peterson et al., 1992a). Although the precise mechanisms by which the gene mutations lead to the neurobehavioral syndrome remain unknown, several studies have implicated dysfunction of basal ganglia dopamine systems. A postmortem neurochemical survey of three LND brains revealed a profound depletion of dopamine in the caudate, putamen, globus pallidus, and accumbens (Lloyd et al., 1981). More recently, positron emission tomography studies have indicated that a deficiency of nigrostriatal dopamine fiber arborization in the basal ganglia may underlie the decreased dopamine levels in LND (Ernst et al., 1996 ; Wong et al., 1996) ; and a quantitative MRI study showed abnormally small basal ganglia (Harris et al., 1998).

Several animal models have been developed for studies of LND (Jinnah et al., 1990), including two different strains of mice carrying mutations in the HPRT gene (Hooper et al., 1987 ; Kuehn et al., 1987). These mice have a complete deficiency of HPRT enzyme activity in the brain and secondary changes in purine metabolism similar to those that occur in LND (Jinnah et al., 1993). In addition, several studies have shown that these mice have reductions in basal ganglia dopamine (Finger et al., 1988 ; Dunnett et al., 1989 ; Williamson et al., 1991 ; Jinnah et al., 1992). However, the dopamine deficit has varied widely in the different studies from 20% to >60%. As basal ganglia dopamine content varies approximately twofold among different inbred strains of normal mice (Sanghera et al., 1990 ; Skrinskaya et al., 1992 ; Puglisi-Allegra and Cabib, 1997), it is possible that the lower dopamine levels observed in the HPRT mutants reflect strain-dependent variation rather than a pathologic effect from the HPRT gene mutation. This strain-dependent variation among normal mouse strains has recently been recognized as a major confounding variable influencing the interpretation of the neurochemical, pharmacological, and behavioral changes in transgenic and knockout mice (Gerlai, 1996). In the present studies, we have investigated the interactive effects between different mouse strains and mutation of the HPRT gene on basal ganglia dopamine systems.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. TH, AADC, and ChAT activity in three mouse strains
  6. DISCUSSION
  7. Acknowledgements

Animals

For comparisons involving the effect of background strain and HPRT gene mutation, founder mice carrying a deletion mutation in the HPRT gene were originally derived from a 129/Ola × Swiss-Webster cross (Hooper et al., 1987). They were subsequently bred congenically with 129/J, C57BL/6J, DBA/2J, or outbred Swiss-Webster mice for 8, 12, 4, and 8 generations, respectively. Mice carrying a retrovirus-induced mutation in the HPRT gene (Kuehn et al., 1987) were originally derived from 129/SvEv stock and maintained inbred on this same strain. Stock strains for breeding were obtained from Jackson Laboratories (Bar Harbor, ME, U.S.A.). Animals were housed 4-12 per cage with a 12-h light/dark cycle and free access to food and water. Normal (HPRT+) and HPRT-deficient (HPRT-) mice were identified by measuring HPRT enzyme activity in a small sample of blood removed from the tail (Jinnah et al., 1993).

For comparisons involving the effect of age, mice carrying the deletion mutation were maintained by congenic breeding with the C57BL/6J for >20 generations. Tissue samples were collected at 2, 4, 6, and 12 weeks of age. All animal care and procedures were conducted in accordance with recent guidelines established by the NIH and our own institutional review committees.

Tissue collection

Animals were killed by decapitation. Brains were removed and the caudoputamen and mesolimbic striatum (accumbens with olfactory tubercle) were rapidly dissected on an ice-cooled platform. Tissue was stored frozen at -70°C. Frozen tissues were then homogenized in 10-20 volumes of chilled 50 mM NaH2PO4 buffer, pH 7.0. An aliquot was rapidly adjusted to 0.1 M sodium acetate and centrifuged to sediment particulate matter before HPLC analysis. Another aliquot was refrozen at -70°C for enzyme assays.

Biochemical assays

Monoamines were measured by HPLC with electrochemical detection, with sensors set at 150, 250, 350, and 500 mV (ESA, Chelmsford, MA, U.S.A.). Exactly 10 μl of tissue extract was injected onto a C18 reverse-phase MD-150 column (ESA) and eluted at a flow rate of 0.6 ml/min for 20 min. The mobile phase consisted of 1.7 mM 1-octanesulfonic acid sodium, 25 μM EDTA, 0.01% tetraethylammonium, and 8% acetonitrile in 75 mM sodium phosphate buffer, pH 2.9.

Tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) activities were measured by in vitro methods (Jinnah et al., 1994). Aromatic amino acid decarboxylase (AADC) activity was measured by a modification of the CO2 trapping method of Lunan and Mitchell (1969). The final reaction mixture contained 250 μM unlabeled l-DOPA, 25 μMdl-[14C]DOPA (spec. act. 45-55 mCi/mmol), 200 μM pyridoxal phosphate, and 0.1 M KH2PO4 buffer, pH 7.0, in a total volume of 120 μl. The [14C]CO2 evolved was trapped by using a rubber stopper with a center well containing a piece of filter paper saturated with 100 μl of methylbenzethonium hydroxide. The reaction was started by adding 20 μl of tissue extract to 100 μl of reaction substrate and allowed to proceed for 30 min at 37°C. The reaction was terminated by the addition of 100 μl of 6 M trichloroacetic acid, followed by a 2-h incubation to allow complete CO2 trapping. The filters were then transferred to vials containing 6 ml of Ecoscint and counted.

Data analysis

Results for individual tests were analyzed by multivariate ANOVA followed by post hoc Tukey tests where appropriate.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. TH, AADC, and ChAT activity in three mouse strains
  6. DISCUSSION
  7. Acknowledgements

Dopamine depletion in five mouse strains

Significant variation in caudoputamen dopamine was observed among the five different strains of mice tested (Fig. 1). In normal mice, the highest levels were observed in the Swiss-Webster mice and the lowest levels were observed in the 129/SvEv mice. Similar to previous studies comparing normal mouse strains (Sanghera et al., 1990 ; Skrinskaya et al., 1992 ; Puglisi-Allegra and Cabib, 1997), the absolute variation among the different strains was approximately twofold. Despite a twofold variation in the caudoputamen dopamine content of the normal mice, all HPRT- mice showed consistently lower dopamine levels than their strain-matched counterparts. The results were analyzed by two-way ANOVA with strain and HPRT status as main factors. ANOVA confirmed significant main effects for both strain (F = 30.3, p < 0.001) and HPRT status (F = 383.5, p < 0.001). There was also a significant interaction between strain and HPRT status, indicating that some strains were more significantly affected than others (F = 7.4, p < 0.001). Caudoputamen dopamine was reduced in the HPRT- mice by 61.1, 56.2, 50.7, 53.4, and 52.3% in the Swiss-Webster, C57BL/6J, 129/J, DBA/2J, and 129/SvEv strains, respectively, with an overall average reduction of 54.7%.

image

Figure 1. Caudoputamen dopamine concentrations in different HPRT- mouse strains. Dopamine was measured by HPLC with electrochemical detection in dissected caudoputamen of normal (black columns) and HPRT- (gray columns) mice of the Swiss-Webster, C57BL/6J, 129/J, DBA/2J, DBA/2J, and 129/SvEv strains. Results are average ± SE values from six normal and six HPRT- mice, shown for each strain except the C57BL/6J strain, for which there were seven normal and seven HPRT- mice. Post hoc Tukey tests after two-way ANOVA indicated statistically significant differences between normal and HPRT- mice of each strain as indicated by the asterisks (p < 0.01).

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Significant variation in mesolimbic dopamine was also observed among the different strains of mice (Fig. 2). Unexpectedly, the strains with the highest levels of dopamine in the caudoputamen were not necessarily those with high levels of dopamine in the mesolimbic areas. As a result, there was little correlation between the dopamine contents of the caudoputamen and mesolimbic areas across the different strains. However, the HPRT- mice again showed consistently lower dopamine levels than their strain-matched counterparts. Similar to results obtained from the caudoputamen, two-way ANOVA confirmed significant main effects for both strain (F = 64.4, p < 0.001) and HPRT status (F = 83.8, p < 0.001), as well as a significant interaction between strain and HPRT status (F = 4.2, p < 0.006). Mesolimbic dopamine was reduced in the HPRT- mice by 31.6, 35.5, and 38.6% in the Swiss-Webster, 129/J, and DBA/2J strains, respectively, with an overall average reduction of 35.2%. Although the HPRT- mice of the C57BL/6J and 129/SvEv strains showed a trend toward lower values, the decreases were not statistically significant.

image

Figure 2. Mesolimbic dopamine concentrations in different HPRT- mouse strains. Dopamine was measured by HPLC with electrochemical detection in dissected ventral striata (accumbens and olfactory tubercle) of normal (black columns) and HPRT- (gray columns) mice of the Swiss-Webster, C57BL/6J, 129/J, DBA/2J, and 129/SvEv strains. Results are average ± SE values from six normal and six HPRT- mice, shown for each strain except the C57BL/6J strain, for which there were seven normal and seven HPRT- mice. Post hoc Tukey tests after two-way ANOVA indicated statistically significant differences between normal and HPRT- mice of the Swiss-Webster (p < 0.001), 129/J (p < 0.02), and DBA/2J (p < 0.001) strains as indicated by asterisks. However, differences between normal and HPRT- mice of the C57BL/6J and 129/SvEv strains were not significant (p > 0.2).

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Age-dependent dopamine depletion in the C57BL/6J strain

Although background strain appears to modify the severity of dopamine loss in both the caudoputamen and mesolimbic areas of HPRT- mice, this variation appears unlikely to explain the wide range of dopamine loss reported for these mutants in prior studies. Although it is difficult to compare studies performed in different laboratories, it appears likely that additional variables may be involved. To determine if the magnitude of dopamine reduction depends on the age at which it is measured, caudoputamen dopamine was measured in normal and HPRT- mice of the C57BL/6J strain at different postnatal ages. In both normal and mutant mice, caudoputamen dopamine increased from birth until ~6 weeks of age (Fig. 3). Caudoputamen dopamine was not significantly different between the normal and mutant mice at 2 weeks of age, but a progressively wider difference emerged between 4 and 12 weeks of age.

image

Figure 3. Caudoputamen dopamine at different postnatal ages in normal and HPRT- C57BL/6J mice. Dopamine was measured by HPLC with electrochemical detection in dissected caudoputamen of normal (•) and HPRT- mice (○) at 2, 4, 6, and 12 weeks of age. Results are average ± SE values from eight normal and six to eight HPRT- mice shown for each time point. Two-way ANOVA revealed significant effects for age (F = 89.5, p < 0.001) and HPRT status (F = 85.5, p < 0.001), as well as a significant interaction between age and HPRT status (F = 11.8, p < 0.001). Asterisks denote statistically significant differences (p < 0.01) between normal and HPRT- mice at 4, 6, and 12 weeks of age.

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TH, AADC, and ChAT activity in three mouse strains

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. TH, AADC, and ChAT activity in three mouse strains
  6. DISCUSSION
  7. Acknowledgements

Previous studies of HPRT- mice of the C57BL/6J strain have indicated that the decrease in caudoputamen dopamine is accompanied by a decrease in the activity of TH, the first and rate-limiting enzyme in dopamine synthesis (Jinnah et al., 1994). To determine if the decrease in TH enzyme activity is a general feature of HPRT deficiency in the mouse, we compared caudoputamen TH activity in strains derived from Swiss-Webster, C57BL/6J, and 129/J mice. TH activity varied approximately twofold among different strains and was significantly reduced in HPRT- mice of all strains (Table 1). A two-way ANOVA with strain and HPRT status as main factors revealed a significant effect of strain (F = 253.3, p < 0.001), HPRT status (F = 113.6, p < 0.001), and a significant interaction between strain and HPRT status (F = 7.3, p < 0.003). TH activity was reduced by 37.3, 33.1, and 22.4% in the Swiss-Webster, C57BL/6J, and 129/SvEv strains, respectively, with an overall average reduction of 30.9%.

Table 1. Neurotransmitter synthetic enzymes in the caudoputamen TH, AADC, and ChAT were measured by in vitro methods. The Swiss-Webster and C57BL/6J mice carry the HPRT deletion mutation, whereas the 129/SvEv mice carry the retrovirus mutation. The number of animals used for each determination is shown in parentheses. Results are average data ± SE values.
 TH (pmol/min/mg)AADC (nmol/min/mg)ChAT (nmol/min/mg)
Swiss-Webster   
HPRT+ (n = 6)69.7 ± 3.3418.7 ± 17.59.2 ± 0.6
HPRT- (n = 6)43.7 ± 4.4325.9 ± 23.26.5 ± 0.4
Percent change-37.3%-22.2%-29.3%
C57BL/6J   
HPRT+ (n = 5)118.0 ± 10.4720.9 ± 27.115.3 ± 1.7
HPRT- (n = 5)79.5 ± 7.2410.5 ± 29.312.8 ± 1.1
Percent change-33.1%-43.1%-11.2%
129/SvEv   
HPRT+ (n = 6)168.5 ± 4.2904.5 ± 25.815.6 ± 0.3
HPRT- (n = 6)130.7 ± 2.7614.8 ± 34.314.2 ± 0.3
Percent change-22.4%-32.0%-6.6%

AADC, the second enzyme in the synthetic pathway for dopamine, also varied approximately twofold among different strains (Table 1). Similar to results obtained for TH, AADC activity was significantly reduced in the HPRT- mice. ANOVA revealed a significant effect of strain (F = 128.9, p < 0.001), HPRT status (F = 125.1, p < 0.001), and a significant interaction between strain and HPRT status (F = 11.3, p < 0.001). AADC activity was reduced by 22.2, 43.1, and 32.0% in the Swiss-Webster, C57BL/6J, and 129/SvEv strains, respectively, with an overall average reduction of 32.4%.

Previous studies have also indicated a small decrease in caudoputamen ChAT, the enzyme responsible for the synthesis of acetylcholine (Jinnah et al., 1994). ChAT activity varied less than twofold among different strains and was slightly but significantly reduced in all the HPRT- strains (Table 1). ANOVA revealed a significant effect of strain (F = 35.3, p < 0.001) and HPRT status (F = 263.2, p < 0.001), but the interaction between strain and HPRT status was not significant (F = 1.2, p > 0.2). Although statistically significant, the absolute decrease in ChAT activity of the HPRT- mice was quite small, averaging 16% across all strains.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. TH, AADC, and ChAT activity in three mouse strains
  6. DISCUSSION
  7. Acknowledgements

These results confirm that HPRT deficiency in the mouse is associated with a significant reduction in basal ganglia dopamine levels. Three variables appear to influence the magnitude of this reduction : strain, basal ganglia subregion, and age. Consistent with prior studies, background strain influenced the dopamine levels in normal mice, suggesting the existence of genetic controls over basal ganglia dopamine content (Sanghera et al., 1990 ; Skrinskaya et al., 1992 ; Puglisi-Allegra and Cabib, 1997). This control is likely to be polygenic, although a few major loci may comprise a large proportion of the variation. All the HPRT- mice had significantly lower basal ganglia dopamine levels than their strain-matched counterparts, demonstrating that a single locus can have a marked effect on brain dopamine content, even when superimposed on normal strain-dependent variation.

The severity of dopamine loss in the HPRT- mice depended not only on background strain, but also on basal ganglia subregion. In comparison with normal mice, dopamine was reduced in the HPRT- mice by an average of 55% in the caudoputamen and 35% in the mesolimbic areas. The caudoputamen was significantly affected in all five strains examined, with minor variations in severity among the different strains. In contrast, the mesolimbic areas were significantly affected in only three of the five strains. This result demonstrates that different basal ganglia subregions are differentially susceptible to HPRT deficiency, and that background strain can modify the expression of the mutation in some regions more than others.

The severity of dopamine reductions measurable in the HPRT- mice is also dependent on the age at which they are examined. Consistent with prior studies of normal mice, caudoputamen dopamine levels in C57BL/6J mice increased from birth through 6 weeks of age (Roffler-Tarlov and Graybiel, 1987 ; Voorn et al., 1988). This increase is thought to reflect the extension and maturation of dopamine fibers extending from the midbrain into the caudoputamen (Roffler-Tarlov and Graybiel, 1987 ; Voorn et al., 1988). The finding that dopamine depletion in the HPRT- mice does not become apparent until 4 weeks of age suggests that dopamine depletion is the result of a defect in dopamine fiber arborization (Lloyd et al., 1981). This hypothesis is further supported by reductions in TH, AADC (Table 1), and dopamine uptake sites (Jinnah et al., 1994). Precise histologic methods will be required to address this hypothesis more directly.

The HPRT- mouse has served primarily as a genetic and biochemical model of LND, because these animals do not display any overt neurobehavioral abnormalities. Despite the absence of obvious neurobehavioral defects, these studies demonstrate that the brains of these animals cannot be considered normal. Because of the occurrence of abnormalities in the purine and dopamine systems, these mice provide an invaluable tool for studying the mechanisms by which HPRT deficiency affects brain purine and dopamine systems.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. TH, AADC, and ChAT activity in three mouse strains
  6. DISCUSSION
  7. Acknowledgements

We thank Dr. David Whittingham (MRC Experimental Embryology and Teratology Unit, St. George's Hospital Medical School, London, U.K.) for generously providing mice carrying the HPRT deletion mutation. We also thank Dr. Michael Kuehn (Experimental Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD, U.S.A.) for providing mice carrying the retrovirus-mediated HPRT mutation. This study was supported by the Lesch-Nyhan Syndrome Children's Research Foundation (H.A.J., T.F., and G.R.B.) and NIH 1K08NS0198501 (H.A.J.).

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