D.D. Schmorrow et al. (Eds.): Augmented Cognition, HCII 2009, LNAI 5638, pp. 818–825, 2009. © Springer-Verlag Berlin Heidelberg 2009 Long Term Repair of Learning Disability through Short-Term Reduction of CNS Inhibition H. Craig Heller 1 , Damien Colas 1 , Norman F. Ruby 1 , Fabian Fernandez 2 , Bayarasaikhan Chuluun 1 , Martina Blank 2 , and Craig C. Garner 2 1 Departments of Biology 2 Psychiatry and Behavioral Sciences Stanford University, Stanford, CA 94305 hcheller@stanford.edu, cgarner@stanford.edu Abstract. Learning disabilities are serious societal problems contributing to a loss of quality of life for affected individuals and their families. We hypothe- sized that the learning disability in Down Syndrome and perhaps in other neurodegenerative disorders is due to an imbalance between inhibitory and ex- citatory 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. 1 Introduction The incidence of intellectual disability is about 1-2% in western countries, and the resulting health costs, opportunity costs, and loss of productivity are in the tens of billions of dollars/year. In about three-fourths, one of several hundred single gene disorders is the cause; the remainder is due to chromosomal abnormalities, malnutri- tion, fetal alcohol exposure or brain injury. One of the most common, Down syn- drome has been found to affect 1 of every 700 live births. We are following up on previous work [1] that advanced and tested the hypothesis that the cognitive dysfunction in Down Syndrome is due to an excess of inhibitory tone in the CNS. It was shown that reducing inhibitory tone with non-competitive GABA A antagonists (pentylenetetrazole, bilobilide, and picrotoxin) restored learning ability in a mouse model of Down Syndrome (TsDn65 mice), and that this improve- ment extended months beyond the treatment regimen. The long-term efficacy of these treatments indicated that they induced a major and lasting neuroplastic effect. One