Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

Cell Rep. 2020 Jan 28;30(4):1152-1163.e4. doi: 10.1016/j.celrep.2019.12.065.


Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.

Keywords: Down syndrome; Trisomy 21; executive function; functional connectivity; gamma; hippocampus; memory; prefrontal cortex; theta.

MeSH terms

  • Animals
  • Chromosomes, Human, Pair 21 / genetics
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / physiopathology*
  • Disease Models, Animal
  • Down Syndrome / genetics*
  • Electroencephalography
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology*
  • Humans
  • Male
  • Memory, Short-Term / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Spatial Memory / physiology*
  • Theta Rhythm / genetics
  • Trisomy / genetics*
  • Trisomy / physiopathology


  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases