Skip to main content

Advertisement

SpringerLink
Log in

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Roizen NJ, Patterson D (2003) Down’s syndrome. Lancet 361:1281–1289. doi:10.1016/S0140-6736(03)12987-X

    Article  PubMed  Google Scholar 

  2. Rueda N, Flórez J, Martínez-Cué C (2012) Mouse models of Down syndrome as a tool to unravel the causes of mental disabilities. Neural Plast 2012:584071. doi:10.1155/2012/584071

    PubMed Central  PubMed  Google Scholar 

  3. Sturgeon X, Gardiner KJ (2011) Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions. Mamm Genome 22:261–271. doi:10.1007/s00335-011-9321-y

    Article  PubMed  Google Scholar 

  4. Roubertoux PL, Carlier M (2010) Mouse models of cognitive disabilities in trisomy 21 (Down syndrome). Am J Med Genet C Semin Med Genet 154C:400–416. doi:10.1002/ajmg.c.30280

    Article  PubMed  Google Scholar 

  5. Holtzman DM, Santucci D, Kilbridge J et al (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA 93:13333–13338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Costa AC, Walsh K, Davisson MT (1999) Motor dysfunction in a mouse model for Down syndrome. Physiol Behav 68:211–220

    Article  CAS  PubMed  Google Scholar 

  7. Escorihuela RM, Fernández-Teruel A, Vallina IF et al (1995) A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. Neurosci Lett 199:143–146

    Article  CAS  PubMed  Google Scholar 

  8. Reeves RH, Irving NG, Moran TH et al (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet 11:177–184. doi:10.1038/ng1095-177

    Article  CAS  PubMed  Google Scholar 

  9. Escorihuela RM, Vallina IF, Martínez-Cué C et al (1998) Impaired short- and long-term memory in Ts65Dn mice, a model for down syndrome. Neurosci Lett 247:171–174

    Article  CAS  PubMed  Google Scholar 

  10. Demas GE, Nelson RJ, Krueger BK, Yarowsky PJ (1998) Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice. Behav Brain Res 90:199–201

    Article  CAS  PubMed  Google Scholar 

  11. Demas GE, Nelson RJ, Krueger BK, Yarowsky PJ (1999) Spatial memory deficits in segmental trisomic Ts65Dn mice. Behav Brain Res 82:85–92

    Article  Google Scholar 

  12. Sago H, Carlson EJ, Smith DJ et al (2000) Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr Res 48:606–613. doi:10.1203/00006450-200011000-00009

    Article  CAS  PubMed  Google Scholar 

  13. Hyde LA, Frisone DF, Crnic LS (2001) Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function. Behav Brain Res 118:53–60

    Article  CAS  PubMed  Google Scholar 

  14. Siarey RJ, Stoll J, Rapoport SI, Galdzicki Z (1997) Altered long-term potentiation in the young and old Ts65Dn mouse, a model for down Syndrome. Neuropharmacology 36:1549–1554

    Article  CAS  PubMed  Google Scholar 

  15. Kleschevnikov AM, Belichenko PV, Villar AJ et al (2004) Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J Neurosci 24:8153–8160. doi:10.1523/JNEUROSCI.1766-04.2004

    Article  CAS  PubMed  Google Scholar 

  16. Siarey RJ, Carlson EJ, Epstein CJ et al (1999) Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology 38:1917–1920

    Article  CAS  PubMed  Google Scholar 

  17. Clark S, Schwalbe J, Stasko MR et al (2006) Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Exp Neurol 200:256–261. doi:10.1016/j.expneurol.2006.02.005

    Article  CAS  PubMed  Google Scholar 

  18. Insausti AM, Megías M, Crespo D et al (1998) Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of Down syndrome. Neurosci Lett 253:175–178

    Article  CAS  PubMed  Google Scholar 

  19. Lorenzi HA, Reeves RH (2006) Hippocampal hypocellularity in the Ts65Dn mouse originates early in development. Brain Res 1104:153–159. doi:10.1016/j.brainres.2006.05.022

    Article  CAS  PubMed  Google Scholar 

  20. Masliah E, Terry RD, Alford M, DeTeresa R (1990) Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections. J Histochem Cytochem 38:837–844

    Article  CAS  PubMed  Google Scholar 

  21. Eastwood SL, Harrison PJ (2001) Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res Bull 55:569–578

    Article  CAS  PubMed  Google Scholar 

  22. Belichenko NP, Belichenko PV, Kleschevnikov AM et al (2009) The “Down syndrome critical region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of down syndrome. J Neurosci 29:5938–5948. doi:10.1523/JNEUROSCI.1547-09.2009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Belichenko PV, Masliah E, Kleschevnikov AM et al (2004) Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome. J Comp Neurol 480:281–298. doi:10.1002/cne.20337

    Article  PubMed  Google Scholar 

  24. Belichenko PV, Kleschevnikov AM, Salehi A et al (2007) Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol 504:329–345. doi:10.1002/cne.21433

    Article  CAS  PubMed  Google Scholar 

  25. Pérez-Cremades D, Hernández S, Blasco-Ibáñez JM et al (2010) Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome. J Neural Transm 117:445–455. doi:10.1007/s00702-010-0376-9

    Article  PubMed  Google Scholar 

  26. Kurt MA, Davies DC, Kidd M et al (2000) Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice. Brain Res 858:191–197

    Article  CAS  PubMed  Google Scholar 

  27. Kleschevnikov AM, Belichenko PV, Gall J et al (2012) Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 45:683–691. doi:10.1016/j.nbd.2011.10.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Fernandez F, Morishita W, Zuniga E et al (2007) Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci 10:411–413. doi:10.1038/nn1860

    CAS  PubMed  Google Scholar 

  29. Scott-McKean JJ, Costa ACS (2011) Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine. Learn Mem 18:774–778. doi:10.1101/lm.024182.111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Chen R (2004) Interactions between inhibitory and excitatory circuits in the human motor cortex. Exp Brain Res 154:1–10. doi:10.1007/s00221-003-1684-1

    Article  PubMed  Google Scholar 

  31. Hensch TK, Fagiolini M (2005) Excitatory-inhibitory balance and critical period plasticity in developing visual cortex. Prog Brain Res 147:115–124. doi:10.1016/S0079-6123(04)47009-5

    Article  CAS  PubMed  Google Scholar 

  32. Trevelyan AJ, Watkinson O (2005) Does inhibition balance excitation in neocortex? Prog Biophys Mol Biol 87:109–143. doi:10.1016/j.pbiomolbio.2004.06.008

    Article  PubMed  Google Scholar 

  33. Akerman CJ, Cline HT (2007) Refining the roles of GABAergic signaling during neural circuit formation. Trends Neurosci 30:382–389. doi:10.1016/j.tins.2007.06.002

    Article  CAS  PubMed  Google Scholar 

  34. Benes FM, Berretta S (2001) GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25:1–27. doi:10.1016/S0893-133X(01)00225-1

    Article  CAS  PubMed  Google Scholar 

  35. Rubenstein JLR, Merzenich MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255–267

    Article  CAS  PubMed  Google Scholar 

  36. Rippon G, Brock J, Brown C, Boucher J (2007) Disordered connectivity in the autistic brain: challenges for the “new psychophysiology”. Int J Psychophysiol 63:164–172. doi:10.1016/j.ijpsycho.2006.03.012

    Article  PubMed  Google Scholar 

  37. Zold CL, Larramendy C, Riquelme LA, Murer MG (2007) Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson’s disease experimental models. Eur J Neurosci 26:1267–1279. doi:10.1111/j.1460-9568.2007.05754.x

    Article  PubMed  Google Scholar 

  38. Reynolds GP, Warner CE (1988) Amino acid neurotransmitter deficits in adult Down’s syndrome brain tissue. Neurosci Lett 94:224–227

    Article  CAS  PubMed  Google Scholar 

  39. Risser D, Lubec G, Cairns N, Herrera-Marschitz M (1997) Excitatory amino acids and monoamines in parahippocampal gyrus and frontal cortical pole of adults with Down syndrome. Life Sci 60:1231–1237

    Article  CAS  PubMed  Google Scholar 

  40. Hernández S, Gilabert-Juan J, Blasco-Ibáñez JM et al (2012) Altered expression of neuropeptides in the primary somatosensory cortex of the Down syndrome model Ts65Dn. Neuropeptides 46:29–37. doi:10.1016/j.npep.2011.10.002

    Article  PubMed  Google Scholar 

  41. Hunter CL, Bachman D, Granholm A-C (2004) Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome. Ann Neurol 56:675–688. doi:10.1002/ana.20250

    Article  CAS  PubMed  Google Scholar 

  42. Lockrow J, Prakasam A, Huang P et al (2009) Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol 216:278–289. doi:10.1016/j.expneurol.2008.11.021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Chakrabarti L, Best TK, Cramer NP et al (2010) Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome. Nat Neurosci 13:927–934. doi:10.1038/nn.2600

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Liu DP, Schmidt C, Billings T, Davisson MT (2003) Quantitative PCR genotyping assay for the Ts65Dn mouse model of Down syndrome. Biotechniques 35:1170–4, 1176, 1178 passim

  45. Lantos TA, Görcs TJ, Palkovits M (1995) Immunohistochemical mapping of neuropeptides in the premamillary region of the hypothalamus in rats. Brain Res Brain Res Rev 20:209–249

    Article  CAS  PubMed  Google Scholar 

  46. Csiffáry A, Görcs TJ, Palkovits M (1990) Neuropeptide Y innervation of ACTH-immunoreactive neurons in the arcuate nucleus of rats: a correlated light and electron microscopic double immunolabeling study. Brain Res 506:215–222

    Article  PubMed  Google Scholar 

  47. Varea E, Blasco-Ibáñez JM, Gómez-Climent MA et al (2007) Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex. Neuropsychopharmacology 32:803–812. doi:10.1038/sj.npp.1301183

    Article  CAS  PubMed  Google Scholar 

  48. West MJ (1993) New stereological methods for counting neurons. Neurobiol Aging 14:275–285

    Article  CAS  PubMed  Google Scholar 

  49. Nacher J, Alonso-Llosa G, Rosell D, McEwen B (2002) PSA-NCAM expression in the piriform cortex of the adult rat. Modulation by NMDA receptor antagonist administration. Brain Res 927:111–121

    Article  CAS  PubMed  Google Scholar 

  50. Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263

    Article  CAS  PubMed  Google Scholar 

  51. Földy C, Aradi I, Howard A, Soltesz I (2004) Diversity beyond variance: modulation of firing rates and network coherence by GABAergic subpopulations. Eur J Neurosci 19:119–130

    Article  PubMed  Google Scholar 

  52. Howell MD, Gottschall PE (2012) Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican. ASN Neuro. doi:10.1042/AN20110037

  53. Begenisic T, Spolidoro M, Braschi C et al (2011) Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome. Front Cell Neurosci 5:29. doi:10.3389/fncel.2011.00029

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Best TK, Cramer NP, Chakrabarti L et al (2012) Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome. Exp Neurol 233:749–757. doi:10.1016/j.expneurol.2011.11.033

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Kleschevnikov AM, Belichenko PV, Faizi M et al (2012) Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists. J Neurosci 32:9217–9227. doi:10.1523/JNEUROSCI.1673-12.2012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Rueda N, Llorens-Martín M, Flórez J et al (2010) Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J Alzheimers Dis 21:277–290. doi:10.3233/JAD-2010-100240

    CAS  PubMed  Google Scholar 

  57. Popov VI, Kleschevnikov AM, Klimenko OA et al (2011) Three-dimensional synaptic ultrastructure in the dentate gyrus and hippocampal area CA3 in the Ts65Dn mouse model of Down syndrome. J Comp Neurol 519:1338–1354. doi:10.1002/cne.22573

    Article  CAS  PubMed  Google Scholar 

  58. Whittle N, Sartori SB, Dierssen M et al (2007) Fetal Down syndrome brains exhibit aberrant levels of neurotransmitters critical for normal brain development. Pediatrics 120:e1465–e1471. doi:10.1542/peds.2006-3448

    Article  PubMed  Google Scholar 

  59. Seidl R, Cairns N, Singewald N et al (2001) Differences between GABA levels in Alzheimer’s disease and Down syndrome with Alzheimer-like neuropathology. Naunyn Schmiedebergs Arch Pharmacol 363:139–145

    Article  CAS  PubMed  Google Scholar 

  60. Freund TF, Buzsáki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470. doi:10.1002/(SICI)1098-1063(1996)6:4<347:AID-HIPO1>3.0.CO;2-I

    Article  CAS  PubMed  Google Scholar 

  61. Acsády L, Görcs TJ, Freund TF (1996) Different populations of vasoactive intestinal polypeptide-immunoreactive interneurons are specialized to control pyramidal cells or interneurons in the hippocampus. Neuroscience 73:317–334

    Article  PubMed  Google Scholar 

  62. Blasco-Ibáñez JM, Martínez-Guijarro FJ, Freund TF (1998) Enkephalin-containing interneurons are specialized to innervate other interneurons in the hippocampal CA1 region of the rat and guinea-pig. Eur J Neurosci 10:1784–1795

    Article  PubMed  Google Scholar 

  63. Stafstrom CE (1993) Epilepsy in Down syndrome: clinical aspects and possible mechanisms. Am J Ment Retard 98(Suppl):12–26

    PubMed  Google Scholar 

  64. Blasco-Ibáñez JM, Freund TF (1997) Distribution, ultrastructure, and connectivity of calretinin-immunoreactive mossy cells of the mouse dentate gyrus. Hippocampus 7:307–320. doi:10.1002/(SICI)1098-1063(1997)7:3<307:AID-HIPO6>3.0.CO;2-H

    Article  PubMed  Google Scholar 

  65. Sutula T, Cascino G, Cavazos J et al (1989) Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 26:321–330. doi:10.1002/ana.410260303

    Article  CAS  PubMed  Google Scholar 

  66. Blümcke I, Suter B, Behle K et al (2000) Loss of hilar mossy cells in Ammon’s horn sclerosis. Epilepsia 41(Suppl 6):S174–S180

    Article  PubMed  Google Scholar 

  67. Caserta MT (1994) Neuropeptide Y immunoreactive neurons in murine trisomy 16 cortical cultures. Plasticity of expression and differentiation. Mol Chem Neuropathol 22:197–210

    Article  CAS  PubMed  Google Scholar 

  68. Hill JM, Ades AM, McCune SK et al (2003) Vasoactive intestinal peptide in the brain of a mouse model for Down syndrome. Exp Neurol 183:56–65

    Article  CAS  PubMed  Google Scholar 

  69. Sahir N, Brenneman DE, Hill JM (2006) Neonatal mice of the Down syndrome model, Ts65Dn, exhibit upregulated VIP measures and reduced responsiveness of cortical astrocytes to VIP stimulation. J Mol Neurosci 30:329–340. doi:10.1385/JMN:30:3:329

    Article  CAS  PubMed  Google Scholar 

  70. Ross MH, Galaburda AM, Kemper TL (1984) Down’s syndrome: is there a decreased population of neurons? Neurology 34:909–916

    Article  CAS  PubMed  Google Scholar 

  71. Kobayashi K, Emson PC, Mountjoy CQ et al (1990) Cerebral cortical calbindin D28K and parvalbumin neurones in Down’s syndrome. Neurosci Lett 113:17–22

    Article  CAS  PubMed  Google Scholar 

  72. Pueschel SM, Louis S, McKnight P (1991) Seizure disorders in Down syndrome. Arch Neurol 48:318–320

    Article  CAS  PubMed  Google Scholar 

  73. Prasher VP (1995) Epilepsy and associated effects on adaptive behaviour in adults with Down syndrome. Seizure 4:53–56

    Article  CAS  PubMed  Google Scholar 

  74. Johannsen P, Christensen JE, Goldstein H et al (1996) Epilepsy in Down syndrome–prevalence in three age groups. Seizure 5:121–125

    CAS  PubMed  Google Scholar 

  75. Goldberg-Stern H, Strawsburg RH, Patterson B et al (2001) Seizure frequency and characteristics in children with Down syndrome. Brain Dev 23:375–378

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study has been founded by Jerome Lejeune Foundation, The Spanish Ministry of Science and Innovation BFU2012-32512, MICINN-PIM2010ERN 00577/NEUCONNECT In the frame of ERA-NET NEURON, Generalitat Valenciana ACOMP/2012/229 and PROMETEO 2013/069.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Neurobiology Unit, Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Dr. Moliner, 50, 46100, Burjassot, Spain

    Samuel Hernández-González, Raúl Ballestín, Rosa López-Hidalgo, Javier Gilabert-Juan, José Miguel Blasco-Ibáñez, Carlos Crespo, Juan Nácher & Emilio Varea

  2. Genetics Department, Universitat de València, CIBERSAM, INCLIVA, Valencia, Spain

    Javier Gilabert-Juan

Authors
  1. Samuel Hernández-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raúl Ballestín
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosa López-Hidalgo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Javier Gilabert-Juan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José Miguel Blasco-Ibáñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos Crespo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Nácher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Emilio Varea
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emilio Varea.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hernández-González, S., Ballestín, R., López-Hidalgo, R. et al. Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn. Neurochem Res 40, 151–164 (2015). https://doi.org/10.1007/s11064-014-1479-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1479-8

Keywords

Search

Navigation