Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

Abstract

Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.

Single cell ATAC-seq identifies broad changes in neuronal abundance and chromatin accessibility in Down Syndrome

“…Specifically, we observed that dopamine-receptor expressing interneurons were affected disproportionately relative to other clusters. Interestingly, our data falls in closer agreement to the studies of Hernandez-Gonzalez et al 38 , which used similarly aged 4-month-old adult mice, than to those of Chakrabarti et al 37 , which observed defects in Somatostatin+ interneurons in 1-4-week-old mice. Our data identified no changes in Somatostatin+ and Parvalbumin+ interneurons in adult Ts65Dn mice.…”

“…3b). This finding agrees with reports that interneurons are more abundant in DS 37,38 . Specifically, we observed a large change in INc8 and INc9, which are Drd2 and Drd1 positive medium spiny neurons, respectively, and INc10 and INc11.…”

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

“…While they found no alterations in the numerical density of PV‐Ir interneurons in the PML, they detected a significant increase in glutamic acid decarboxylase (GAD67, i.e. a marker for GABAergic neurons) staining in the DGC layer in Ts65Dn mice compared with controls (Hernandez‐Gonzalez et al, ).…”

Early increased density of cyclooxygenase-2 (COX-2) immunoreactive neurons in Down syndrome

“…This apparent discrepancy could be explained attending to three main facts: (a) the analysis of the increased expression of COX-2 observed in the hippocampus of some animal models of insult, such ischemia, which induces an increase in the expression of COX-2 and neurogenesis reflects that the phenotype of the newly generated cells are mainly glia cells [28]; (b) the second possibility is related to the excess of cellular activity observed in DS [10] as well in the Ts65Dn model (Carbonell in preparation), this overactivation could be the basis of the increased expression of COX-2 and (c) the dysregulation observed in the balance between excitation and inhibition observed in DS [3,12,25]. This dysregulation leads to an increase in some inhibitory neurons, including the so-called IS cells [12,13], which inhibits other inhibitory neurons generating an over-activation that is related with the high prevalence of epilepsy in individuals with DS [30] and could be related to the increased expression of COX-2 observed in neurons in the Ts65Dn model.…”