GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: Exploring the role of App

Hippocampus. 2016 Dec;26(12):1641-1654. doi: 10.1002/hipo.22664. Epub 2016 Oct 24.

Abstract

It has been suggested that increased GABAergic innervation in the hippocampus plays a significant role in cognitive dysfunction in Down syndrome (DS). Bolstering this notion, are studies linking hyper-innervation of the dentate gyrus (DG) by GABAergic terminals to failure in LTP induction in the Ts65Dn mouse model of DS. Here, we used extensive morphometrical methods to assess the status of GABAergic interneurons in the DG of young and old Ts65Dn mice and their 2N controls. We detected an age-dependent increase in GABAergic innervation of dentate granule cells (DGCs) in Ts65Dn mice. The primary source of GABAergic terminals to DGCs somata is basket cells (BCs). For this reason, we assessed the status of these cells and found a significant increase in the number of BCs in Ts65Dn mice compared with controls. Then we aimed to identify the gene/s whose overexpression could be linked to increased number of BCs in Ts65Dn and found that deleting the third copy of App gene in Ts65Dn mice led to normalization of the number of BCs in these mice. Our data suggest that App overexpression plays a major role in the pathophysiology of GABAergic hyperinnervation of the DG in Ts65Dn mice. © 2016 Wiley Periodicals, Inc.

Keywords: GABA; Ts65Dn; basket cells; down syndrome; parvalbumin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Aging / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cyclin-Dependent Kinase 5 / metabolism
  • Dentate Gyrus / metabolism
  • Dentate Gyrus / pathology*
  • Disease Models, Animal
  • Down Syndrome / metabolism
  • Down Syndrome / pathology*
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology*
  • Immunohistochemistry
  • Interneurons / metabolism
  • Interneurons / pathology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Parvalbumins / metabolism
  • Receptors, Kainic Acid / metabolism
  • Synapses / metabolism
  • Synapses / pathology
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Gluk1 kainate receptor
  • Parvalbumins
  • Receptors, Kainic Acid
  • gamma-Aminobutyric Acid
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse