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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.
Highlights
Down syndrome (DS) is a high-incidence genetic pathology caused by triplication of human chromosome 21
To obtain information regarding this issue we examined the size of the mossy fiber system in the stratum lucidum of field CA3
In field CA3 of Ts65Dn mice there was a reduction in the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which is in line with the reduction in the density of non-glutamatergic synapses in the stratum lucidum and suggests a reduced inhibitory control on CA3 pyramidal neurons
Summary
Down syndrome (DS) is a high-incidence genetic pathology caused by triplication of human chromosome 21. Accumulating evidence in DS mouse models clearly shows severe neurogenesis impairment in the major brain neurogenic regions (see [1]), suggesting that defective neurogenesis may be a key determinant of brain hypotrophy and mental retardation. To the Ts65Dn mouse model of DS, human fetuses with DS exhibit proliferation impairment in various brain regions [2,3,4], which validates the use of this model to study trisomy-linked brain alterations. Evidence in humans and mouse models of DS shows severe dendritic alterations that appear to correlate with the cognitive profile [1], [5], [6]. Though defective neurogenesis is probably a crucial determinant of mental retardation, dendritic hypotrophy and spine density reduction with consequent connectivity alterations are likely to be important actors
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