Abstract
Interneurons play a significant role in the functional organization of the striatum and some of them display marked plastic changes in dopamine-depleted conditions. Here, we applied immunohistochemistry on brain sections from 6-hydroxydopamine (6-OHDA) mouse model of Parkinson’s disease and sham animals to characterize the regional distribution and the morphological and neurochemical changes of striatal interneurons expressing the calcium-binding protein calretinin (CR). Two morphological subtypes of calretinin-immunostained (CR +) interneurons referred, respectively, as small- and medium-sized CR + interneurons were detected in 6-OHDA- and sham-lesioned animals. The small cells (9–12 µm) prevail in the anterior and dorsal striatal regions; they stain intensely for CR and display a single slightly varicose and moderately arborized process. The medium-sized CR + interneurons (15–20 µm) are more numerous than the small CR + cells and rather uniformly distributed within the striatum; they stain weakly for CR and display 2–3 long, slightly varicose and poorly branched dendrites. The density of medium CR + interneurons is significantly decreased in the dopamine-depleted striatum (158 ± 15 neurons/mm3), when compared to sham animals (370 ± 41 neurons/mm3), whereas that of the small-sized CR + interneurons is unchanged (174 ± 46 neurons/mm3 in 6-OHDA-lesioned striatum and 164 ± 22 neurons/mm3 in sham-lesioned striatum). The nucleus accumbens is populated only by medium-sized CR + interneurons, which are distributed equally among the core and shell compartments and whose density is unaltered after dopamine denervation. Our results provide the first evidence that the medium-sized striatal interneurons expressing low level of CR are specifically targeted by dopamine denervation, while the small and intensely immunoreactive CR + cells remain unaffected. These findings suggest that high expression of the calcium-binding protein CR might protect striatal interneurons against an increase in intracellular calcium level that is believed to arise from altered glutamate corticostriatal transmission in Parkinson’s disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Antunes MS, Cattelan Souza L, Ladd FVL, Ladd A, Moreira AL, Bortolotto VC, Silva MRP, Araujo SM, Prigol M, Nogueira CW, Boeira SP (2020) Hesperidin ameliorates anxiety-depressive-like behavior in 6-OHDA model of Parkinson’s disease by regulating striatal cytokine and neurotrophic factors levels and dopaminergic innervation loss in the striatum of mice. Mol Neurobiol 57(7):3027–3041. https://doi.org/10.1007/s12035-020-01940-3
Avila-Costa MR, Colín-Barenque L, Aley-Medina P, Valdez AL, Librado JL, Martinez EF, Fortoul TI (2005) Bilateral increase of perforated synapses after unilateral dopamine depletion. Int J Neurosci 115(1):79–86
Bernacer J, Prensa L, Gimenez-Amaya JM (2012) Distribution of GABAergic interneurons and dopaminergic cells in the functional territories of the human striatum. PLoS ONE 7(1):e30504. https://doi.org/10.1371/journal.pone.0030504
Blandini F, Porter RH, Greenamyre JT (1996) Glutamate and Parkinson’s disease. Mol Neurobiol 12(1):73–94. https://doi.org/10.1007/BF02740748
Calabresi P, Pisani A, Mercuri NB, Bernardi G (1996) The corticostriatal projection: from synaptic plasticity to dysfunctions of the basal ganglia. Trends Neurosci 19(1):19–24. https://doi.org/10.1016/0166-2236(96)81862-5
Cepeda C, Colwell CS, Itri JN, Gruen E, Levine MS (1998) Dopaminergic modulation of early signs of excitotoxicity in visualized rat neostriatal neurons. Eur J Neurosci 10(11):3491–3497. https://doi.org/10.1046/j.1460-9568.1998.00357.x
Choi DW (2005) Neurodegeneration: cellular defences destroyed. Nature 433(7027):696–698. https://doi.org/10.1038/433696a
Cicchetti F, Prensa L, Wu Y, Parent A (2000) Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington’s disease. Brain Res Brain Res Rev 34(1–2):80–101. https://doi.org/10.1016/s0165-0173(00)00039-4
Dayer AG, Cleaver KM, Abouantoun T, Cameron HA (2005) New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J Cell Biol 168(3):415–427. https://doi.org/10.1083/jcb.200407053
Ding Y, Won L, Britt JP, Lim SA, McGehee DS, Kang UJ (2011) Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proc Natl Acad Sci USA 108(2):840–845. https://doi.org/10.1073/pnas.1006511108
Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisén J (2014) Neurogenesis in the striatum of the adult human brain. Cell 156:1072–1083. https://doi.org/10.1016/j.cell.2014.01.044
Fass B, Butcher LL (1981) Evidence for a crossed nigrostriatal pathway in rats. Neurosci Lett 22(2):109–113
Fieblinger T, Graves SM, Sebel LE, Alcacer C, Plotkin JL, Gertler TS, Chan CS, Heiman M, Greengard P, Cenci MA, Surmeier DJ (2014) Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nat Commun 5:5316. https://doi.org/10.1038/ncomms6316
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(2):356–372. https://doi.org/10.1006/exnr.1997.6724
Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego
Gagnon D, Petryszyn S, Sanchez MG, Bories C, Beaulieu JM, De Koninck Y, Parent A, Parent M (2017) Striatal neurons expressing D1 and D2 receptors are morphologically distinct and differently affected by dopamine denervation in mice. Sci Rep 7:41432. https://doi.org/10.1038/srep41432
Garas FN, Kormann E, Shah RS, Vinciati F, Smith Y, Magill PJ, Sharott A (2018) Structural and molecular heterogeneity of calretinin-expressing interneurons in the rodent and primate striatum. J Comp Neurol 526(5):877–898. https://doi.org/10.1002/cne.24373
García-Fiñana M, Cruz-Orive LM, Mackay CE, Pakkenberg B, Roberts N (2003) Comparison of MR imaging against physical sectioning to estimate the volume of human cerebral compartments. Neuroimage 18(2):505–516
Gerfen C, Bolam J (2010) Handbook of Basal Ganglia Structure and Function, Chapter 20, The neuroanatomical organization of the basal ganglia. Academic Press
German DC, Manaye KF, Sonsalla PK, Brooks BA (1992) Midbrain dopaminergic cell loss in Parkinson’s disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells. Ann NY Acad Sci 648:42–62. https://doi.org/10.1111/j.1749-6632.1992.tb24523.x
Gomez G, Escande MV, Suarez LM, Rela L, Belforte JE, Moratalla R, Murer MG, Gershanik OS, Taravini IRE (2019) Changes in dendritic spine density and inhibitory perisomatic connectivity onto medium spiny neurons in L-dopa-induced dyskinesia. Mol Neurobiol 56(9):6261–6275. https://doi.org/10.1007/s12035-019-1515-4
Graveland GA, DiFiglia M (1985) The frequency and distribution of medium-sized neurons with indented nuclei in the primate and rodent neostriatum. Brain Res 327(1–2):307–311
Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology–reconsidered. J Microsc 193(Pt 3):199–211. https://doi.org/10.1046/j.1365-2818.1999.00457.x
Hooks BM, Papale AE, Paletzki RF, Feroze MW, Eastwood BS, Couey JJ, Winnubst J, Chandrashekar J, Gerfen CR (2018) Topographic precision in sensory and motor corticostriatal projections varies across cell type and cortical area. Nat Commun 9(1):3549. https://doi.org/10.1038/s41467-018-05780-7
Huot P, Levesque M, Parent A (2007) The fate of striatal dopaminergic neurons in Parkinson’s disease and Huntington’s chorea. Brain 130(Pt 1):222–232. https://doi.org/10.1093/brain/awl332
Hussain Z, Johnson LR, Totterdell S (1996) A light and electron microscopic study of NADPH-diaphorase-, calretinin- and parvalbumin-containing neurons in the rat nucleus accumbens. J Chem Neuroanat 10(1):19–39
Inoue KI, Miyachi S, Nishi K, Okado H, Nagai Y, Minamimoto T, Nambu A, Takada M (2019) Recruitment of calbindin into nigral dopamine neurons protects against MPTP-Induced parkinsonism. Mov Disord off J Mov Disord Soc 34(2):200–209. https://doi.org/10.1002/mds.107
Jedrzejewska A, Wierzba-Bobrowicz T, Olejniczak P, Poszwińska Z, Dymecki J (1990) Ultrastructure and immunocytochemistry of left and right nigrostriatal system after lesion of right side of substantia nigra of rat. Adv Neurol 53:41–49
Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, Vaccarino FM (2010) Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J Comp Neurol 518(3):277–291. https://doi.org/10.1002/cne.22206
Kawaguchi Y, Wilson CJ, Augood SJ, Emson PC (1995) Striatal interneurones: chemical, physiological and morphological characterization. Trends Neurosci 18(12):527–535
Kiritani T, Wickersham IR, Seung HS, Shepherd GM (2012) Hierarchical connectivity and connection-specific dynamics in the corticospinal-corticostriatal microcircuit in mouse motor cortex. J Neurosci 32(14):4992–5001. https://doi.org/10.1523/JNEUROSCI.4759-11.2012
Lee J, Park K, Lee S, Whang K, Kang M, Park C, Huh Y (2002) Differential changes of calcium binding proteins in the rat striatum after kainic acid-induced seizure. Neurosci Lett 333(2):87–90. https://doi.org/10.1016/s0304-3940(02)00987-4
Luzzati F, De Marchis S, Fasolo A, Peretto P (2006) Neurogenesis in the caudate nucleus of the adult rabbit. J Neurosci 26(2):609–621. https://doi.org/10.1523/JNEUROSCI.4371-05.2006
Ma Y, Zhan M, Ouyang L, Li Y, Chen S, Wu J, Chen J, Luo C, Lei W (2014) The effects of unilateral 6-OHDA lesion in medial forebrain bundle on the motor, cognitive dysfunctions and vulnerability of different striatal interneuron types in rats. Behav Brain Res 266:37–45. https://doi.org/10.1016/j.bbr.2014.02.039
Meshul CK, Emre N, Nakamura CM, Allen C, Donohue MK, Buckman JF (1999) Time-dependent changes in striatal glutamate synapses following a 6-hydroxydopamine lesion. Neuroscience 88(1):1–16. https://doi.org/10.1016/s0306-4522(98)00189-4
Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4):687–702. https://doi.org/10.1016/j.neuron.2011.05.001
Mitchell IJ, Lawson S, Moser B, Laidlaw SM, Cooper AJ, Walkinshaw G, Waters CM (1994) Glutamate-induced apoptosis results in a loss of striatal neurons in the parkinsonian rat. Neuroscience 63(1):1–5. https://doi.org/10.1016/0306-4522(94)90002-7
Mura A, Feldon J, Mintz M (2000) The expression of the calcium binding protein calretinin in the rat striatum: effects of dopamine depletion and L-DOPA treatment. Exp Neurol 164(2):322–332. https://doi.org/10.1006/exnr.2000.7441
Nikolaus S, Larisch R, Beu M, Forutan F, Vosberg H, Müller-Gärtner HW (2003) Bilateral increase in striatal dopamine D2 receptor density in the 6-hydroxydopamine-lesioned rat: a serial in vivo investigation with small animal PET. Eur J Nucl Med Mol Imaging 30(3):390–395. https://doi.org/10.1007/s00259-002-1056-2
Oorschot DE (2013) The percentage of interneurons in the dorsal striatum of the rat, cat, monkey and human: a critique of the evidence. Basal Ganglia 3(1):19–24. https://doi.org/10.1016/j.baga.2012.11.001
Parent M, Parent A (2006) Single-axon tracing study of corticostriatal projections arising from primary motor cortex in primates. J Comp Neurol 496(2):202–213. https://doi.org/10.1002/cne.20925
Parent A, Cicchetti F, Beach TG (1995) Calretinin-immunoreactive neurons in the human striatum. Brain Res 674(2):347–351. https://doi.org/10.1016/0006-8993(95)00124-9
Petryszyn S, Beaulieu JM, Parent A, Parent M (2014) Distribution and morphological characteristics of striatal interneurons expressing calretinin in mice: a comparison with human and nonhuman primates. J Chem Neuroanat 59–60:51–61. https://doi.org/10.1016/j.jchemneu.2014.06.002
Petryszyn S, Di Paolo T, Parent A, Parent M (2016) The number of striatal cholinergic interneurons expressing calretinin is increased in parkinsonian monkeys. Neurobiol Dis 95:46–53. https://doi.org/10.1016/j.nbd.2016.07.002
Pisani A, Bernardi G, Ding J, Surmeier DJ (2007) Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci 30(10):545–553. https://doi.org/10.1016/j.tins.2007.07.008
Revishchin AV, Okhotin VE, Korochkin LI, Pavlova GV (2010a) A new population of calretinin-positive cells, presumptively neurons, with polymorphous spines in the mouse forebrain. Neurosci Behav Physiol 40(5):541–552. https://doi.org/10.1007/s11055-010-9295-3
Revishchin AV, Okhotin VE, Pavlova GV (2010b) New calretinin-positive cells with polymorphous spines in the mouse forebrain during early postnatal ontogeny. Neurosci Behav Physiol 40(8):833–840. https://doi.org/10.1007/s11055-010-9349-6
Rivera A, Alberti I, Martín AB, Narváez JA, de la Calle A, Moratalla R (2002) Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor subtype. Eur J Neurosci 16(11):2049–2058
Rymar VV, Sasseville R, Luk KC, Sadikot AF (2004) Neurogenesis and stereological morphometry of calretinin-immunoreactive GABAergic interneurons of the neostriatum. J Comp Neurol 469(3):325–339. https://doi.org/10.1002/cne.11008
Schmitz C, Hof PR (2000) Recommendations for straightforward and rigorous methods of counting neurons based on a computer simulation approach. J Chem Neuroanat 20(1):93–114. https://doi.org/10.1016/s0891-0618(00)00066-1
Schwaller B (2014) Calretinin: from a “simple” Ca(2+) buffer to a multifunctional protein implicated in many biological processes. Front Neuroanat 8:3. https://doi.org/10.3389/fnana.2014.00003
Suarez LM, Solis O, Carames JM, Taravini IR, Solis JM, Murer MG, Moratalla R (2014) L-DOPA treatment selectively restores spine density in dopamine receptor D2-expressing projection neurons in dyskinetic mice. Biol Psychiatry 75(9):711–722. https://doi.org/10.1016/j.biopsych.2013.05.006
Tepper JM, Koos T, Ibanez-Sandoval O, Tecuapetla F, Faust TW, Assous M (2018) Heterogeneity and diversity of striatal GABAergic interneurons: update 2018. Front Neuroanat 12:91. https://doi.org/10.3389/fnana.2018.00091
Trouche S, Koren V, Doig NM, Ellender TJ, El-Gaby M, Lopes-Dos-Santos V, Reeve HM, Perestenko PV, Garas FN, Magill PJ, Sharott A, Dupret D (2019) A hippocampus-accumbens tripartite neuronal motif guides appetitive memory in space. Cell 176(6):1393-1406 e1316. https://doi.org/10.1016/j.cell.2018.12.037
Unal B, Shah F, Kothari J, Tepper JM (2015) Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway. Brain Struct Funct 220(1):331–349. https://doi.org/10.1007/s00429-013-0658-8
Wei B, Nie Y, Li X, Wang C, Ma T, Huang Z, Tian M, Sun C, Cai Y, You Y, Liu F, Yang Z (2011) Emx1-expressing neural stem cells in the subventricular zone give rise to new interneurons in the ischemic injured striatum. Eur J Neurosci 33(5):819–830. https://doi.org/10.1111/j.1460-9568.2010.07570.x
Wu Y, Parent A (2000) Striatal interneurons expressing calretinin, parvalbumin or NADPH-diaphorase: a comparative study in the rat, monkey and human. Brain Res 863(1–2):182–191. https://doi.org/10.1016/s0006-8993(00)02135-1
Acknowledgements
We thank Marie-Josée Wallman for technical support. This study was supported by research grants from the Canadian Institutes of Health Research (CIHR 153068 to M.P.) and the Natural Sciences and Engineering Research Council of Canada (NSERC 06264 and 522690 to M.P.). The authors have no conflict of interest to declare.
Funding
This study was supported by research grants from the Canadian Institutes of Health Research (CIHR 153068 to M.P.) and the Natural Sciences and Engineering Research Council of Canada (NSERC 06264 and 522690 to M.P.).
Author information
Authors and Affiliations
Contributions
SP was in charge of running experiments. SP and LS were in charge of data and statistical analyses. DG provided guidance for stereology. MP designed experiments and wrote the manuscript. AP revised the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interest to declare.
Ethical approval
All protocols were approved by the Institutional Animal Care and Use Committee (Comité de Protection des Animaux de l’Université Laval, #2019-287/VRR-18-107) and all procedures involving animals and their care were made in accordance with the Canadian Council on Animal Care’s Guide to the Care and Use of Experimental Animals (Ed2).
Consent for publication
All authors have read and approved the final version of the manuscript.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Petryszyn, S., Saidi, L., Gagnon, D. et al. The density of calretinin striatal interneurons is decreased in 6-OHDA-lesioned mice. Brain Struct Funct 226, 1879–1891 (2021). https://doi.org/10.1007/s00429-021-02298-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-021-02298-5