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Chronic Quinolinic Acid Lesions in Rats Closely Resemble Huntington’S Disease

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Chronic Quinolinic Acid Lesions in Rats Closely Resemble Huntington’S Disease The Journal of Neuroscience, June 1991, fI(6): 1649-l 659 Chronic Quinolinic Acid Lesions in Rats Closely Resemble Huntington’s Disease M. Flint Beal,’ Robert J. Ferrante,1*2 Kenton J. Swartz,1s3 and Neil W. Kowall’ ‘Neurochemistry and Experimental Neuropathology Laboratories, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, *C. S. Kubik Laboratory of Neuropathology, James Homer Wright Laboratories, Massachusetts General Hospital, Boston, Massachusetts 02114, and 3Program in Neuroscience, Harvard Medical School and Harvard University, Boston, Massachusetts 02115 We previously found a relative sparing of somatostatin and populations. Striatal medium-sized spiny neurons containing neuropeptide Y neurons 1 week after producing striatal le- the neurochemicalmarkers GABA, substanceP, dynorphin, and sions with NMDA receptor agonists. These results are similar enkephalin are preferentially affected (Beal and Martin, 1986; to postmortem findings in Huntington’s disease (HD), though Ferrante et al., 1987b; Beal et al., 1988b). In contrast, medium- in this illness there are two- to threefold increases in striatal sized aspiny neuronscontaining the neuropeptidessomatostatin somatostatin and neuropeptide Y concentrations, which may and neuropeptide Y, and largeaspiny neuronscontaining ChAT be due to striatal atrophy. In the present study, we examined activity, are spared(Dawbam et al., 1985; Ferrante et al., 1985, the effects of striatal excitotoxin lesions at 6 months and 1 1987a; Beal et al., 1988b). Dopaminergic and serotonergic af- yr, because these lesions exhibit striatal shrinkage and at- ferent projections are also spared (Spokes, 1980; Beal et al., rophy similar to that occurring in HD striatum. At 6 months 1990b). and 1 yr, lesions with the NMDA receptor agonist quinolinic A suitable animal model of HD must replicate thesefeatures. acid (QA) resulted in significant increases (up to twofold) in Initial studies with kainic acid (KA)-induced lesionsshowed a concentrations of somatostatin and neuropeptide Y immu- striking resemblanceto HD (Coyle and Schwartz, 1976;McGeer noreactivity, while concentrations of GABA, substance P im- and McGeer, 1976). Intrastriatal injections resultedin neuronal munoreactivity, and ChAT activity were significantly re- loss and gliosis, with reductions in markers of intrinsic striatal duced. In contrast, somatostatin and neuropeptide Y neurons,yet a preservation ofdopaminergic afferents.We found, concentrations did not increase 6 months after kainic acid however, that these lesions were an imperfect model of HD, (KA) or cy-amino-3-hydroxy-&methyl-isoxazole4-propionic becausethey resulted in a significant depletion of somatostatin acid (AMPA) lesions. At both 6 months and 1 yr, QA lesions levels and a lossof somatostatin neurons(Beal et al., 1985). We showed striking sparing of NADPH-diaphorase neurons as subsequentlyfound that lesionsproduced by NMDA receptor compared with both AMPA and KA lesions, neither of which agonistssuch as quinolinic acid (QA) provided a better model showed preferential sparing of these neurons. Long-term QA of HD, becausethey result in relative sparing of somatostatin lesions also resulted in significant increases in concentra- and neuropeptide Y levels, despitesignificant depletionsof both tions of both 5-HT and 5-hydroxyindoleacetic acid (HIAA), GABA and substanceP levels (Beal et al., 1986a, 1989b). In similar to findings in HD. Chronic QA lesions therefore close- HD, however, there are two- to threefold increasesin concen- ly resemble the neurochemical features of HD, because they trations of somatostatin and neuropeptide Y, rather than the result in increases in somatostatin and neuropeptide Y and mere preservation of levels observed 1 week after lesionswith in 5-HT and HIAA. These findings strengthen the possibility NMDA receptor agonists(Beal et al., 1989b). It is possiblethat that an NMDA receptor-mediated excitotoxic process could the increased levels reflect preservation of somatostatin-neu- play a role in the pathogenesis of HD. ropeptide Y neurons, in combination with striatal atrophy and shrinkage. Following long-term excitotoxin lesions, there are Huntington’s disease(HD) is an autosomaldominant inherited marked striatal shrinkageand atrophy (Zaczek et al., 1978; Isac- neurodegenerativedisorder that usually begins in midlife and son et al., 1984, 1985; Bjorklund et al., 1986). In the present is characterized by involuntary choreiform movements, cog- study, we therefore examined the effects of lesions at both nitive impairment, and emotional disturbance (Bruyn, 1968). 6-month and I-yr survival times. The major site of pathology in HD is the striatum, where up to 90% of the neurons may be depleted (Vonsattel et al., 1985). Within the striatum there is differential vulnerability of neuronal Materials and Methods KA andQA wereobtained from Sigma(St. Louis,MO), whilea-amino- 3-hydroxy-5-methyl-isoxazole-4-propionicacid (AMPA) wasobtained Received Aug. 22, 1990; revised Dec. 26, 1990; accepted Jan. 4, 1991. from ResearchBiochemicals (Wayland, MA). Male Sprague-Dawley The secretarial assistance of Sharon Melanson is gratefully acknowledged. This rats (CharlesRiver) weighing150-l 75 gm wereanesthetized with pen- work was supported by NINDS Grant 16367 (Huntington’s Disease Center With- tobarbital(50 mg/kg, i.p.). Compoundswere dissolved in phosphate- out Walls). bufferedsaline (pH, 7.4) andwere injected in a volumeof 1 ~1into the Correspondence should be addressed to Dr. M. Flint Beal, Neurology Research left striatumat the coordinates8.4 mm anterior, 2.6 mm lateral,and 4, Massachusetts General Hospital, Boston, MA 02114. 4.5 mm ventral to the dura (Bealet al., 1989b).Injections were made Copyright 0 1991 Society for Neuroscience 0270-6474/91/l 11649-l 1$03.00/O with a lo-r1 Hamiltonsyringe fit with a 30-gaugeblunt-tipped needle. 1650 Beal et al. * Chronic Quinolinic Acid Striatal Lesions -_ linolinic Acid Kainic Acid AMPA 240 nmol 7.5 nmol 22.5 nmol Puinolinic Acid Kainic Acid AMPA 240 nmol 7.5 nmol 22.5 nmol Figure 1. Effects of QA, KA, and AMPA striatal lesions at 6 months. I The QA lesions resulted in significant increases in both somatostatin Figure 2. Neurochemical measurements in cerebral cortex overlying (XI) and neuropeptide Y (NPYLI) concentrations while substance P 6-month striatal excitotoxin lesions. There were no significant changes (SPLl), GABA, taurine, and ChAT activity were significantly reduced. in any of the compounds examined. Abbreviations are as in Figure 1. Neither KA nor AMPA lesions resulted in significant increases in so- matostatin or neuropeptide Y concentrations. *, P < 0.05; **, P < 0.0 1; ***, P < 0.001. combination with immunocytochemical staining for Met-enkephalin (ENK), as previously described (Beal et al., 1989b). Examination ofthe lesions at both 6 months and 1 yr showed a marked All injections were made over 1 min, and the needle was left in place shrinkage of the lesioned striatum. Total protein measurements on the for a further 2 min before being slowly withdrawn. side of the lesion were reduced by approximately 50%. The large lesion Three groups of eight animals were lesioned with QA (240 nmol), core, in which there are intense gliosis and few remaining neurons at 1 AMPA (22.5 nmol), or KA (7.5 nmol). These animals were killed 6 week, was largely resorbed. The needle track and a small surrounding months after lesions were produced. Two additional groups of eight necrotic region could usually be identified. This was surrounded by a animals lesioned with 240 nmol of QA were allowed to survive for 1 large region of partial neuronal loss and gliosis, which we term the week or 1 yr. Following death, the brains were chilled, and the anterior transition zone. This extended to an area of relatively normal-appearing striatum and overlying cerebral cortex were dissected from a 2-mm- striatum adjacent to the corpus callosum at the periphery of the lesion. thick slice, as previously described (Beal et al., 1986a). Care was taken Within the transition zone, neuronal counts were made by two inde- to exclude the globus pallidus. The left and right striata were placed in pendent observers. A 350 x 500-pm field at 250x magnification was 1 ml chilled 0.1 N HCl. In the animals that survived for 1 yr, the midbrain counted, using an eyepiece graticule. Fields in the transition zone of the (substantia nigra) was also dissected. Tissue samples were subsequently lesioned striatum were compared with fields in the same location in the sonicated, extracted, and assayed for somatostatin-like immunoreactiv- contralateral control (unlesioned) striatum. Counts were made in six ity, neuropeptide Y-like immunoreactivity, substance P-like immuno- fields in each animal and were averaged. Counts were expressed as the reactivity, and GABA as previously described (Arnold et al., 1982; Beal ratio of NADPH-diaphorase-reactive neurons to total neurons (Nissl et al., 1986b Beal and Mazurek, 1987; Ellison et al., 1987a). Mono- stained) or to the number of Met-enkephalin neurons. Statistical com- amines and their metabolites were measured by high-performance liquid parisons were made by ANOVA with post hoc analysis using the Sheffe chromatography with 16-electrode electrochemical detection (ESA CEAS, F test or the nonpaired Student’s t test. The results are expressed as the 55-0650; Matson et al., 1987). Kynurenic acid was measured by high- mean + standard error of the mean. performance liquid chromatography
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