Prenatal NAP+SAL Prevents Developmental Delay in a Mouse Model of Down Syndrome Through Effects on N-methyl-D-aspartic Acid and Gamma-aminobutyric Acid Receptors

Overview

Journal Am J Obstet Gynecol

Publisher Elsevier

Specialty Gynecology & Obstetrics

Date 2009 Mar 31

PMID 19327737

Citations 12

Authors

Joy Vink

Maddelena Incerti

Laura Toso

Robin Roberson

Daniel Abebe

Catherine Y Spong

Affiliations

Soon will be listed here.

Abstract

Objective: Down syndrome (DS) affects 1/800 infants. Prenatal NAPVSIPQ (NAP) and SALLRSIPA (SAL) (NAP+SAL) prevent developmental delay in Ts65Dn mice, a mouse model of DS. We investigated whether this finding involves N-methyl-D-aspartic acid and gamma-aminobutyric acid (GABA) receptor subunits.

Study Design: Pregnant Ts65Dn mice were treated with placebo or NAP+SAL on gestational days 8-12. After developmental delay prevention was shown, 4 trisomic (Ts), 4 control, and 3 Ts+NAP+SAL adult offspring brains (from 3 litters) were collected. Calibrator-normalized real-time polymerase chain reaction was performed using primers for N-methyl-D-aspartic acid subunits NR2A and NR2B, and for GABA subunits GABA(A)alpha5 and GABA(A)beta3 with glyceraldehyde-3-phosphate dehydrogenase standardization. Statistics included analysis of variance and Fisher PLSD with P < .05 as significant.

Results: NR2A, NR2B, and GABA(A)beta3 levels were decreased in Ts vs control (all P < .05). Prenatal NAP+SAL increased NR2A, NR2B, and GABA(A)beta3 to levels similar to control (all P < .05). A significant difference in GABA(A)alpha5 levels was not found.

Conclusion: Prenatal NAP+SAL increases NR2A, NR2B, and GABA(A)beta3 expression in adult DS mice to levels similar to controls. This may explain how NAP+SAL improve developmental milestone achievement.

Citing Articles

Prenatal and Postnatal Therapies for Down's Syndrome and Associated Developmental Anomalies and Degenerative Deficits: A Systematic Review of Guidelines and Trials.

Hasina Z, Wang C Front Med (Lausanne). 2022; 9:910424.

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Quantitative Analysis of Retinal Structure and Function in Two Chromosomally Altered Mouse Models of Down Syndrome.

Victorino D, Scott-McKean J, Johnson M, Costa A Invest Ophthalmol Vis Sci. 2020; 61(5):25.

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Timing of therapies for Down syndrome: the sooner, the better.

Stagni F, Giacomini A, Guidi S, Ciani E, Bartesaghi R Front Behav Neurosci. 2015; 9:265.

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Weaker control of the electrical properties of cerebellar granule cells by tonically active GABAA receptors in the Ts65Dn mouse model of Down's syndrome.

Szemes M, Davies R, Garden C, Usowicz M Mol Brain. 2013; 6:33.

PMID: 23870245 PMC: 3723448. DOI: 10.1186/1756-6606-6-33.

Prospects for improving brain function in individuals with Down syndrome.

Costa A, Scott-McKean J CNS Drugs. 2013; 27(9):679-702.

PMID: 23821040 DOI: 10.1007/s40263-013-0089-3.

References

Reeves R, Irving N, Moran T, WOHN A, Kitt C, Sisodia S . A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995; 11(2):177-84. DOI: 10.1038/ng1095-177. View

Hill J, Ades A, McCune S, Sahir N, Moody E, Abebe D . Vasoactive intestinal peptide in the brain of a mouse model for Down syndrome. Exp Neurol. 2003; 183(1):56-65. DOI: 10.1016/s0014-4886(03)00164-x. View

Toso L, Endres M, Vink J, Abebe D, Brenneman D, Spong C . Learning enhancement with neuropeptides. Am J Obstet Gynecol. 2006; 194(4):1153-8. DOI: 10.1016/j.ajog.2005.12.023. View

Hyde L, Frisone D, Crnic L . Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function. Behav Brain Res. 2001; 118(1):53-60. DOI: 10.1016/s0166-4328(00)00313-2. View

Vink J, Auth J, Abebe D, Brenneman D, Spong C . Novel peptides prevent alcohol-induced spatial learning deficits and proinflammatory cytokine release in a mouse model of fetal alcohol syndrome. Am J Obstet Gynecol. 2005; 193(3 Pt 1):825-9. DOI: 10.1016/j.ajog.2005.02.101. View

Toso L, Cameroni I, Roberson R, Abebe D, Bissell S, Spong C . Prevention of developmental delays in a Down syndrome mouse model. Obstet Gynecol. 2008; 112(6):1242-1251. PMC: 2687469. DOI: 10.1097/AOG.0b013e31818c91dc. View

Spong C, Abebe D, Gozes I, Brenneman D, Hill J . Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome. J Pharmacol Exp Ther. 2001; 297(2):774-9. View

Sago H, Carlson E, Smith D, Rubin E, Crnic L, Huang T . Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr Res. 2000; 48(5):606-13. DOI: 10.1203/00006450-200011000-00009. View

Brenneman D, Spong C, Hauser J, Abebe D, Pinhasov A, Golian T . Protective peptides that are orally active and mechanistically nonchiral. J Pharmacol Exp Ther. 2004; 309(3):1190-7. DOI: 10.1124/jpet.103.063891. View

10.

Best T, Siarey R, Galdzicki Z . Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current. J Neurophysiol. 2006; 97(1):892-900. DOI: 10.1152/jn.00626.2006. View

11.

Bassan M, Zamostiano R, Davidson A, Pinhasov A, Giladi E, Perl O . Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999; 72(3):1283-93. DOI: 10.1046/j.1471-4159.1999.0721283.x. View

12.

Holtzman D, Santucci D, Kilbridge J, Fontana D, Daniels S, Johnson R . Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci U S A. 1996; 93(23):13333-8. PMC: 24093. DOI: 10.1073/pnas.93.23.13333. View

13.

Gozes I, Zamostiano R, Pinhasov A, Bassan M, Giladi E, Steingart R . A novel VIP responsive gene. Activity dependent neuroprotective protein. Ann N Y Acad Sci. 2001; 921:115-8. DOI: 10.1111/j.1749-6632.2000.tb06957.x. View

14.

Barker J, Behar T, Li Y, Liu Q, Ma W, Maric D . GABAergic cells and signals in CNS development. Perspect Dev Neurobiol. 1998; 5(2-3):305-22. View

15.

Demas G, Nelson R, Krueger B, Yarowsky P . Spatial memory deficits in segmental trisomic Ts65Dn mice. Behav Brain Res. 1996; 82(1):85-92. DOI: 10.1016/s0166-4328(97)81111-4. View

16.

Giladi E, Hill J, Dresner E, Stack C, Gozes I . Vasoactive intestinal peptide (VIP) regulates activity-dependent neuroprotective protein (ADNP) expression in vivo. J Mol Neurosci. 2007; 33(3):278-83. DOI: 10.1007/s12031-007-9003-0. View

17.

Spong C, Lee S, McCune S, Gibney G, Abebe D, Alvero R . Maternal regulation of embryonic growth: the role of vasoactive intestinal peptide. Endocrinology. 1999; 140(2):917-24. DOI: 10.1210/endo.140.2.6481. View

18.

Demas G, Nelson R, Krueger B, Yarowsky P . Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice. Behav Brain Res. 1998; 90(2):199-201. DOI: 10.1016/s0166-4328(97)00116-2. View

19.

Perez-Otano I, Ehlers M . Learning from NMDA receptor trafficking: clues to the development and maturation of glutamatergic synapses. Neurosignals. 2004; 13(4):175-89. DOI: 10.1159/000077524. View

20.

Contestabile A, Fila T, Ceccarelli C, Bonasoni P, Bonapace L, Santini D . Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with Down syndrome and in Ts65Dn mice. Hippocampus. 2007; 17(8):665-78. DOI: 10.1002/hipo.20308. View