Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

Abstract

Down's syndrome (DS), with an incidence of one in 800 live births, is the most common genetic disorder associated with mental retardation. This trisomy on chromosome 21 induces a variable phenotype in which the only common feature is the presence of mental retardation. The neural mechanisms underlying mental retardation might include defects in the formation of neuronal networks and neural plasticity. DS patients have alterations in the morphology, the density and the distribution of dendritic spines in the pyramidal neurons of the cortex. Our hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice (a model for DS that mimics most of the structural alterations observed in humans) may be mediated to some extent by changes in their inhibitory inputs. Different types of interneurons control different types of inhibition. Therefore, to understand well the changes in inhibition in DS, it is necessary to study the different types of interneurons separately. We have studied the expression of synaptophysin, Glutamic acid decarboxylase-67 (GAD-67) and calcium-binding protein-expressing cells in the primary somatosensory cortex of 4-5 month old Ts65Dn mice. We have observed an increment of GAD67 immunoreactivity that is related mainly to an increment of calretinin-immunoreactive cells and among them the ones with bipolar morphology. Since there is a propensity for epilepsy in DS patients, this increase in interneurons might reflect an attempt by the system to block overexcitation rather than an increment in total inhibition and could explain the deficit in interneurons and principal cells observed in elderly DS patients.

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

“…At the synaptic level, studies analysing the expression of synaptophysin, a reliable marker for synapses [20,21], in the hippocampus, have shown that the area occupied by this marker is higher in Ts65Dn mice when compared with euploid mice, suggesting an increase in the size of the synapses [22][23][24]. Similar results were observed by our group in the primary somatosensory cortex [25]. When studying the different subtypes of synaptic contacts in cortical regions, Kurt et al [26], analysing the temporal cortex, have observed a reduction in excitatory synapses and a maintenance of inhibitory ones.…”

“…Other reports have shown maintenance in the level of expression of GAD65, but alterations in the efficiency of inhibitory synapses in the hippocampus [27]. However, in other regions, such as the primary somatosensory cortex, it has been observed an increased density of inhibitory contacts [25]. Altogether, these results suggest an imbalance in the levels of inhibition and excitation in the brain of mouse models for DS.…”

“…When studying the different subtypes of synaptic contacts in cortical regions, Kurt et al [26], analysing the temporal cortex, have observed a reduction in excitatory synapses and a maintenance of inhibitory ones. However in our previous report we have observed an increased density of inhibitory elements in the somatosensory cortex [25]. Attending to the hippocampus, previous studies have observed redistribution of contacts on the dendrites of the principal neurons, resulting in an increment of those contacting spines and in a decrease of those contacting dendritic shafts [23].…”

Trisomie 21, Demenz vom Alzheimer-Typ und Epilepsie

“…Im Mäusemodell (Ts65Dn) ergaben sich Hinweise auf eine vermehrte Dichte bipolarer kortikaler Interneurone [47]. Solche (hemmenden) Interneurone füh-ren über eine Inhibition anderer Interneurone letztlich zu einer Aktivierung nachgeschalteter Nervenzellen [47] -ein Argument dafür, dass aus einem Mehr oder Weniger an Interneuronen der Großhirnrinde nicht unmittelbar auf eine verminderte oder verstärkte neuronale Erregbarkeit geschlossen werden darf.…”

“…Solche (hemmenden) Interneurone füh-ren über eine Inhibition anderer Interneurone letztlich zu einer Aktivierung nachgeschalteter Nervenzellen [47] -ein Argument dafür, dass aus einem Mehr oder Weniger an Interneuronen der Großhirnrinde nicht unmittelbar auf eine verminderte oder verstärkte neuronale Erregbarkeit geschlossen werden darf. Zahlreiche Befunde existieren zu Verän-derungen der Dendritenlänge/-verzweigungen und der Struktur dendritischer Dornen bei Nervenzellen von Menschen mit Trisomie 21 sowie im Mäusemodell [6,16,33].…”