Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships

J Comp Neurol. 2007 Oct 1;504(4):329-45. doi: 10.1002/cne.21433.

Abstract

Down syndrome (DS) is caused by trisomy of human chromosome 21. Because Ts65Dn and Ts1Cje mice are segmentally trisomic for a region of mouse chromosome 16, they genetically model DS and are used to study pathogenic mechanisms. Previously, we provided evidence for changes in both the structure and function of pre- and postsynaptic elements in the Ts65Dn mouse. Striking changes were evident in the size of the dendritic spines and in the ability to induce long-term potentiation (LTP) in the fascia dentata (FD). To explore the genetic basis for these changes, we examined Ts1Cje mice, which are trisomic for a completely overlapping but smaller segment of mouse chromosome 16. As in the Ts65Dn mouse, there was a regionally selective decrease in the density of dendritic spines ( approximately 12%), an increase in the size of spine heads ( approximately 26%), a decrease in the length of spine necks ( approximately 26%), and reorganization of inhibitory inputs with a relative decrease in inputs to dendrite shafts and spine heads and a significant increase to the necks of spines (6.4%). Thus, all of the Ts65Dn phenotypes were present, but they were significantly less severe. In contrast, and just as was the case for the Ts65Dn mouse, LTP could not be induced unless the selective gamma-aminobutyric acid (GABA)(A) receptor antagonist picrotoxin was applied. Therefore, there was conservation of important synaptic phenotypes in the Ts1Cje mice. The analysis of data from this and earlier studies points to genotype-phenotype linkages in DS whose complexity ranges from relatively simple to quite complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Brain / physiopathology
  • Cognition Disorders / complications
  • Cognition Disorders / genetics
  • Cognition Disorders / physiopathology*
  • Dendritic Spines / pathology*
  • Dentate Gyrus / pathology
  • Dentate Gyrus / physiopathology
  • Disease Models, Animal
  • Down Syndrome / complications
  • Down Syndrome / genetics
  • Down Syndrome / physiopathology*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Immunohistochemistry
  • Long-Term Potentiation
  • Male
  • Maze Learning
  • Mice
  • Mice, Mutant Strains
  • Neural Inhibition / genetics
  • Neural Pathways / pathology
  • Neural Pathways / physiopathology
  • Organ Size
  • Phenotype
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / physiology
  • Synapses / genetics
  • Synapses / pathology*
  • Trisomy / genetics
  • Trisomy / physiopathology*

Substances

  • Receptors, GABA-A