Advertisement

Long Term Repair of Learning Disability through Short-Term Reduction of CNS Inhibition

  • H. Craig Heller
  • Damien Colas
  • Norman F. Ruby
  • Fabian Fernandez
  • Bayarasaikhan Chuluun
  • Martina Blank
  • Craig C. Garner
Part of the Lecture Notes in Computer Science book series (LNCS, volume 5638)

Abstract

Learning disabilities are serious societal problems contributing to a loss of quality of life for affected individuals and their families. We hypothesized that the learning disability in Down Syndrome and perhaps in other neurodegenerative disorders is due to an imbalance between inhibitory and excitatory tone in the CNS. Specifically, we predicted that reduction of GABA related inhibition would improve learning. We used the TsDn65 mouse model of Down Syndrome and treated adult mice with daily doses of different GABA antagonists. Following treatments learning performance of these mice in several rodent learning tasks was indistinguishable from the performance of wild type mice, and the learning improvement lasted for months after the treatment ended. We are now exploring the mechanism of this durable neuroplastic effect and asking whether it would generalize to other learning disorders or optimize learning in wild type mice.

Keywords

GABA picrotoxin pentylenetetrazole bilobilide flumazinil Down Syndrome TsDn65 mice novel object recognition 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fernandez, F., Morishita, W., Zuniga, E., Nguyen, J., Blank, M., Malenka, R.C., Garner, C.C.: Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411–413 (2007)PubMedGoogle Scholar
  2. 2.
    Siarey, H., Stoll, J., Rapoport, S.I., Galdzicki, Z.: Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology 36, 1549–1554 (1997)CrossRefPubMedGoogle Scholar
  3. 3.
    Costa, A.C.S., Grybko, M.J.: Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: A model of Down syndrome. Neuroscience Letters, 382-317-322 (2005)Google Scholar
  4. 4.
    Kleschevnikov, A.M., Belichenko, P.V., Villar, J.A.J., Epstein, C.J., Malenka, R.C., Mobley, W.C.: Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24, 8153–8160 (2004)CrossRefPubMedGoogle Scholar
  5. 5.
    Izquierdo, I., Da Cunha, C., Medina, J.H.: Endogenous benzodiazepine modulation of memory processes. Neurosci. Biobehav. Rev. 14, 419–424 (1990)CrossRefPubMedGoogle Scholar
  6. 6.
    Wolfman, C., Da Cunha, C., Jerusalinsky, D., Levi de Stein, M., Viola, H., Izquierdo, I., Medina, J.H.: Habituation and inhibitory avoidance training alter brain regional levels of benzodiazepine-like molecules and are affected by intracerebral flumazenil microinjection. Brain Res. 548, 74–80 (1991)CrossRefPubMedGoogle Scholar
  7. 7.
    Polc, P., Jahromi, S.S., Facciponte, G., Pelletier, M.R., Zhang, L., Carlen, P.L.: Benzodiazepine antagonist flumazenil reduces hippocampal epileptiform activity. Neuroreport 6, 1549–1552 (1995)CrossRefPubMedGoogle Scholar
  8. 8.
    Hamaguchi, H., Hashimoto, T., Mori, K., Tayama, M.: Sleep in the Down syndrome. Brain Dev. 11, 399–406 (1989)CrossRefPubMedGoogle Scholar
  9. 9.
    Colas, D., Valletta, J.S., Takimoto-Kimura, R., Nishino, S., Fujiki, N., Mobley, W.C., Mignot, E.: Sleep and EEG features in genetic models of Down syndrome. Neurobiology of Disease 30, 1–7 (2008)CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • H. Craig Heller
    • 1
  • Damien Colas
    • 1
  • Norman F. Ruby
    • 1
  • Fabian Fernandez
    • 2
  • Bayarasaikhan Chuluun
    • 1
  • Martina Blank
    • 2
  • Craig C. Garner
    • 2
  1. 1.Departments of BiologyUSA
  2. 2.Psychiatry and Behavioral SciencesStanford UniversityStanfordUSA

Personalised recommendations