Pharmacotherapy with fluoxetine restores functional connectivity from the dentate gyrus to field CA3 in the Ts65Dn mouse model of down syndrome

PLoS One. 2013 Apr 19;8(4):e61689. doi: 10.1371/journal.pone.0061689. Print 2013.

Abstract

Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45-60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • CA3 Region, Hippocampal / drug effects
  • CA3 Region, Hippocampal / pathology
  • CA3 Region, Hippocampal / physiopathology*
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / pathology
  • Dentate Gyrus / physiopathology*
  • Disease Models, Animal
  • Down Syndrome / drug therapy*
  • Down Syndrome / pathology
  • Down Syndrome / physiopathology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Female
  • Fluoxetine / pharmacology
  • Fluoxetine / therapeutic use*
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / pathology
  • Mossy Fibers, Hippocampal / physiopathology
  • Nerve Net / drug effects
  • Nerve Net / pathology
  • Nerve Net / physiopathology*
  • Recovery of Function / drug effects*
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / pathology

Substances

  • Brain-Derived Neurotrophic Factor
  • Fluoxetine

Grant support

This work was supported by a grant from the “Fondation Jerome Lejeune” to R. B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript