Abstract
The evolution of cellular damage over time and the selective vulnerability of different neuronal subtypes was characterized in the striatum following 30‐minute middle cerebral artery occlusion and reperfusion in the mouse. Using autoradiography we found an increase in the density of [3H]PK11195 binding sites—likely reflecting microglial activation—in the lesion border at 3 days and in the whole striatum from 10 days to 6 weeks. This was accompanied by a distinct loss of [3H]flumazenil and [3H]CGP39653 binding sites from 10 days up to 6 weeks reflecting neuronal loss. Brain ischemia resulted in a substantial loss of medium spiny projection neurons as seen at three days by Nissl staining, TUNEL and immunocytochemistry using antibodies against microtubule‐associated protein (MAP2), NeuN, (μ‐opioid receptors, substance P, Lenkephalin, neurokinin B, choline acetyltransferase, parvalbumin, calretinin and somatostatin. Both patch and matrix compartments were involved in ischemic damage. In contrast, the numbers of cholinergic, GABAergic, and somatostatin‐containing interneurons in the ischemic striatum were not different from those in the contralateral hemisphere at 3 and 14 days. A low density of glutamate receptors, the ability to sequester calcium by calcium‐binding proteins and other hitherto unidentified factors may explain this relative resistance of interneurons to acute ischemia.
Full Text
The Full Text of this article is available as a PDF (1.2 MB).
References
- 1. Andsberg G, Kokaia Z, Klein RL, Muzyczka N, Lindvall O, Mandel RJ (2002) Neuropathological and behavioral consequences of adeno‐associated viral vector‐mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats. Neurobiol Dis 9:187–204. [DOI] [PubMed] [Google Scholar]
- 2. Anholt RRH, Pederson PL, DeSouza EB, Snyder SH (1986) The peripheral‐type benzodiazepine receptor. J Biol Chem 261:576–583. [PubMed] [Google Scholar]
- 3. Araki T, Kato H, Liu XH, Itoyama Y, Kogure K, Kato K (1994) Delayed damage of striatal interneurons after cerebral ischemia in the gerbil. Neurosci Lett 176:17–20. [DOI] [PubMed] [Google Scholar]
- 4. Banati RB, Goerres GW, Myers R, Gunn RN, Turkheimer FE, Kreutzberg GW, Brooks DJ, Jones T, Duncan JS (1999) [11C] (R) ‐PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis. Neurology 15:2199–2203. [DOI] [PubMed] [Google Scholar]
- 5. Banati RB, Myers R, Kreutzberg GW (1997) PK (‘peripheral benzodiazepine’) ‐binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol 15:77–82. [DOI] [PubMed] [Google Scholar]
- 6. Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannonni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzber GW, Jones T, Cuzner ML, Myers R (2000) The peripheral‐type benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 123:2321–2337. [DOI] [PubMed] [Google Scholar]
- 7. Brooks D, Banati RB, Cagnin A, Myers R, Gunn RN, Piccini P, Olanow CW, Jones T, Brooks DJ. In vivo detection of activated microglia by [11C]PD11195‐PET indicates involvement of the globus pallidum in idiopathic Parkinson's disease (1999) In Calne, D.B. , (ed.) Parkinsonism and Related Disorders. Abstracts of the XIII International Congress on Parkinson's Disease, Vancouver, B.C. pp. S56–57, Elsevier Science Ltd, New York . [Google Scholar]
- 8. Calabresi P, Centonze D, Pisani A, Sancesario G, Gubellini P, Marfia GA, Bernardi G (1998) Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: implications for ischaemia and Huntington's disease. Ann Neurol 43:586–597. [DOI] [PubMed] [Google Scholar]
- 9. Centonze D, Marfia GA, Pisani A, Picconi B, Giacomini P, Barnardi G, Calabresi P (2001) Ionic mechanisms underlying differential vulnerability to ischemia in striatal neurons. Progr Neurobiol 63:687–696. [DOI] [PubMed] [Google Scholar]
- 10. Chesselet MF, Gonzales C, Lin CS, Polsky K, Jin BK (1990) Ischemic damage in the striatum of adult gerbils: relative sparing of somatostatinergic and cholinergic interneurons contrasts with loss of efferent neurons. Exp Neurol 110:209–218. [DOI] [PubMed] [Google Scholar]
- 11. Desjardins P, Todd KG, Hazell HA, Butterworth RF (1999) Increased peripheral‐type benzodiazepine receptor sites and mRNA in thalamus of thiamine‐deficient rats. Neurochem Int 35:363–369. [DOI] [PubMed] [Google Scholar]
- 12. Diorio D, Welner SA, Butterworth RF, Meaney MJ, Suranyi‐Cadotte BE (1991) Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex. Neurobiol Aging 12:255–258. [DOI] [PubMed] [Google Scholar]
- 13. Endres M, Meisel A, Biniskiewicz D, Namura S, Prass K, Ruscher K, Lipski A, Jaenisch R, Moskowitz MA, Dirnagl U (2000). DNA methyltransferase contributes to mild ischemic brain injury. J Neurosci 20:3175–3181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Endres M, Namura S, Shimizu‐Sasamata M, Waeber C, Zhang L, Gomez‐Isla T, Hyman BT, Moskowitz MA (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 18:238–247. [DOI] [PubMed] [Google Scholar]
- 15. Figueredo‐Cardenas G, Harris CL, Anderson KD, Reiner A (1998) Relative resistance of striatal neurons containing calbindin or parvalbumin to quinolinic acid‐mediated excitotoxicity compared to other striatal neuron types. Exp Neurol 149:356–72. [DOI] [PubMed] [Google Scholar]
- 16. Fink K, Zhu J, Namura S, Shimizu‐Sasamata M, Endres M, Ma J, Dalkara T, Yuan J, Moskowitz MA (1998) Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation. J Cereb Blood Flow Metab 18:1071–1076. [DOI] [PubMed] [Google Scholar]
- 17. Fonnum R, Storm‐Mathisen J, Divac I (1981) Biochemical evidence for glutamateas neurotransmitter in corticostriatal and corticothalamic fibres in rat brain. Neuroscience 6:863–873. [DOI] [PubMed] [Google Scholar]
- 18. Gavish M, Katz Y, Bar‐Ami S, Weizman R (1992) Biochemical, physiological, and pathological aspects of the peripheral benzodiazepine receptor. J Neurochem 58:1589–1601. [DOI] [PubMed] [Google Scholar]
- 19. Gerfen CR (1992) The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci 15:133–9. [DOI] [PubMed] [Google Scholar]
- 20. Gerhard A, Banati RB, Cagnin A, Brooks DJ (2001) In vivo imaging of activated microglia with [11C]PK11195 positron emission tomography (PET) in idiopathic and atypical Parkinson's disease. Neurology 15:A270. [Google Scholar]
- 21. Goto S, Nagahiro S, Korematsu K, Ushio Y (1993) Striatonigral involvement following transient focal cerebral ischemia in the rats: an immunohistochemical study on a reversible ischemia model. Acta Neuropathol (Berl) 85:515–20. [DOI] [PubMed] [Google Scholar]
- 22. Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13:244–54. [DOI] [PubMed] [Google Scholar]
- 23. Itzhak Y, Baker LL, Norenberg MD (1993) Characterization of the peripheral‐type benzodiazepine receptors in cultured astrocytes: evidence for multiplicity. Glia 9:211–218. [DOI] [PubMed] [Google Scholar]
- 24. Johnston JG, Gerfen CR, Haber SN, van der Kooy D (1990) Mechanisms of striatal pattern formation: conservation of mammalian compartmentalization. Brain Res Dev Brain Res 57:93–102. [DOI] [PubMed] [Google Scholar]
- 25. Junck L, Olson JMM, Ciliax BJ, Koeppe RA, Warkins GL, Jewett DM, McKeever PE, Wieland DM, Kilbourn MR, Starosta‐Rubinstein S, Mancini WR, Kuhl DE, Greenberg HS, Young AB (1989) PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol 15:752–758. [DOI] [PubMed] [Google Scholar]
- 26. Katchanov J, Harms C, Gertz K, Hauck L, Waeber C, Hirt L, Priller J, von Harsdorf R, Brück W, Hörtnagl H, Dirnagl U, Bhide PG, Endres M (2001) Mild cerebral ischemia induces loss of cyclin‐dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. J Neurosci 21:5045–5053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Kawaguchi Y, Wilson CJ, Augood SJ, Emson PC (1995) Striatal interneurones: chemical, physiological and morphological characterization. Trends Neurosci 18:527–35. [DOI] [PubMed] [Google Scholar]
- 28. Kawaguchi Y (1997) Neostriatal cell subtypes and their functional roles. Neurosci Res 27:1–8. [DOI] [PubMed] [Google Scholar]
- 29. Korpi ER, Mihalek RM, Sinkkonen ST, Hauer B, Hevers W, Homanics GE, Sieghart W, Luddens H (2002) Altered receptor subtypes in the forebrain of GABA(A) receptor delta subunit‐deficient mice: recruitment of gamma 2 subunits. Neuroscience 109:733–743. [DOI] [PubMed] [Google Scholar]
- 30. Kuhlman AC, Guilarte TR (2000) Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem 74:1694–1704. [DOI] [PubMed] [Google Scholar]
- 31. Larsson E, Lindvall O, Kokaia Z (2001) Stereological assessment of vulnerability of immunocytochemically identified striatal and hippocampal neurons after global cerebral ischemia in rats. Brain Res 913:117–32. [DOI] [PubMed] [Google Scholar]
- 32. Meade CA, Figueredo‐Cardenas G, Fusco F, Nowak TS Jr, Pulsinelli WA, Reiner A (2000) Transient global ischemia in rats yields striatal projection neuron and interneuron loss resembling that in Huntington's disease. Exp Neurol 166:307–23. [DOI] [PubMed] [Google Scholar]
- 33. Messmer K, Reynolds GP (1998) Increased peripheral benzodiazepine binding sites in the brain of patients with Huntington's disease. Neurosci Lett 241:53–56. [DOI] [PubMed] [Google Scholar]
- 34. Mugnaini M, Van Amsterdam FT, Ratti E, Trist DG, Bowery NG. Regionally different N‐methyl‐D‐aspartate receptors distinguished by ligand binding and quantitative autoradiography of [3H]‐CGP 39653 in rat brain (1996) Br J Pharmacol 119:819–828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Myers R, Manjil LG, Frackowiak RS, Cremer JE (1991) [3H]PK 11195 and the localisation of secondary thalamic lesions following focal ischemia in rat motor cortex. Neurosci Lett 133:20–24. [DOI] [PubMed] [Google Scholar]
- 36. Myers R, Manjil LG; Cullen BM, Price GW, Frackowiak RS, Cremer JE (1991) Macrophage and astrocyte populations in relation to [3H]PK 11195 binding in rat cerebral cortex following a local ischemic lesion. J Cereb Blood Flow Metab 11:314–322. [DOI] [PubMed] [Google Scholar]
- 37. Nitsch C, Scotti A, Sommacal A, Kalt G (1989) GABAergic hippocampal neurons resistant to ischemia‐induced neuronal death contain the Ca2(+)‐binding protein parvalbumin. Neurosci Lett 105:263–8. [DOI] [PubMed] [Google Scholar]
- 38. Olsen RW, Tobin AJ (1990) Molecular biology of GABA‐A receptors. FASEB J 4:1469–1480. [DOI] [PubMed] [Google Scholar]
- 39. Pappata S, Levasseur M, Gunn RN, Myer R, Crouzel C, Syrota A, Jones T, Kreutzberg GW, Banati RB (2000) Thalamic microglial activation in ischemic stroke detected in vivo by PET and 11C‐PK11195 Neurology 15:1052–1054. [DOI] [PubMed] [Google Scholar]
- 40. Pert CB, Kuhar MJ, Snyder SH (1976) Opiate receptor: autoradiographic localization in rat brain Proc Natl Acad Sci U S A 73:3729–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Raghavendra Rao VL, Dogan A, Bowen KK, Dempsey RJ (2000) Traumatic brain injury leads to increased expression of peripheral‐type benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol 161:102–114. [DOI] [PubMed] [Google Scholar]
- 42. Sauvageau A, Desjardins P, Lozeva V, Rose C, Hazell AS, Bouthillier A, Butterworth R (2002) Increased expression of peripheral‐type benzodiazepine receptors in human temporal lobe epilepsy: implications for PET imaging of hippocampal sclerosis. Metab Brain Dis 17:233–241. [DOI] [PubMed] [Google Scholar]
- 43. Stephenson DT, Schober DA, Smaltig EB, Mincy E, Gehlert DR, Clemens JA (1995) Peripheral benzodiazepine receptors are colocalized with activated microglia following transient global forebrain ischemia in the rat. J Neurosci 15:5263–5274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Stroke Therapy Academic Industry Roundtable (STAIR) (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–2758. [DOI] [PubMed] [Google Scholar]
- 45. Tortosa A, Ferrer I (1993) Parvalbumin immunoreactivity in the hippocampus of the gerbil after transient forebrain ischemia: a qualitative and quantitative sequential study. Neuroscience 55:33–43. [DOI] [PubMed] [Google Scholar]
- 46. Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, Antel JP (1997) PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res 15:345–353. [DOI] [PubMed] [Google Scholar]
- 47. Yamada K, Goto S, Oyama T, Yoshikawa M, Nagahiro S, Ushio Y (1995) Striatal cells containing the Ca(2)‐binding protein calretinin (protein 10) in ischemia‐induced neuronal injury. Acta Neuropathol (Berl) 89:172–7. [DOI] [PubMed] [Google Scholar]
- 48. Zoli M, Grimaldi R, Ferrari R, Zini I, Agnati LF (1997) Short‐ and long‐term changes in striatal neurons and astroglia after transient forebrain ischemia in rats. Stroke 28:1049–58. [DOI] [PubMed] [Google Scholar]