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Prevention of Learning Deficit in a Down Syndrome Model

Incerti, Maddalena MD; Toso, Laura MD; Vink, Joy MD; Roberson, Robin; Nold, Christopher MD; Abebe, Daniel; Spong, Catherine Y. MD

doi: 10.1097/AOG.0b013e3182051ca5
Original Research

OBJECTIVE: To evaluate whether peptides given to adult mice with Down syndrome prevent learning deficits, and to delineate the mechanisms behind the protective effect.

METHODS: Ts65Dn mice were treated for 9 days with peptides D-NAPVSIPQ (NAP)+D-SALLRSIPA (SAL) or placebo, and wild-type animals were treated with placebo. Beginning on treatment day 4, the mice were tested for learning using the Morris watermaze. Probe tests for long-term memory were performed on treatment day 9 and 10 days after treatment stopped. Open-field testing was performed before and after the treatment. Calibrator-normalized relative real-time polymerase chain reaction (PCR) with glyceraldehyde-3-phosphate dehydrogenase (GAPD) standardization was performed on the whole brain and hippocampus for activity-dependent neuroprotective protein, vasoactive intestinal peptide (VIP), glial fibrillary acidic protein (GFAP), NR2B, NR2A, and γ-aminobutyric acid type A (GABAA)-α5. Statistics included analysis of variance and the Fisher protected least significant difference, with P<.05 significant.

RESULTS: The Ts65Dn plus placebo animals did not learn over the 5-day period compared with the controls (P<.001). The Ts65Dn +(D-NAP+D-SAL) learned significantly better than the Ts65Dn plus placebo (P<.05), and they retained learning similar to controls on treatment day 9, but not after 10 days of no treatment. Treatment with D-NAP+D-SAL prevented the Ts65Dn hyperactivity. Adult administration of D-NAP+D-SAL prevented changes in activity-dependent neuroprotective protein, intestinal peptide, and NR2B with levels similar to controls (all P<.05).

CONCLUSION: Adult treatment with D-NAP+D-SAL prevented learning deficit in Ts65Dn, a model of Down syndrome. Possible mechanisms of action include reversal of vasoactive intestinal peptide and activity-dependent neuroprotective protein dysregulation, as well as increasing expression of NR2B, thus facilitating learning.

Adult treatment with D-NAPVSIPQ+D-SALLRSIPA prevents learning deficits in Ts65Dn, a model of Down syndrome; possible mechanisms of action include reversal of vasoactive intestinal peptide, activity-dependent neuroprotective protein, and NR2B dysregulation.

From the Unit on Perinatal and Developmental Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, Maryland; the Department of Obstetrics/Gynecology, George Washington University, Washington, District of Columbia; the Division of Maternal Fetal Medicine, Columbia University Medical Center, New York, New York, and the Department of Obstetrics/Gynecology University of Connecticut Health Center, Connecticut.

Supported by the DIR of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institutes of Health (NIH).

Dr. Spong, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article.

Corresponding author: Maddalena Incerti, MD, Unit on Perinatal and Developmental Neurobiology NICHD, NIH Bldg 9/Room 1W125, 9 Memorial Drive, Bethesda, MD 20892-0925; e-mail: maddalena.incerti@gmail.com.

Financial Disclosure The authors did not report any potential conflicts of interest.

© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.