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Intellectual disability in Down syndrome (DS) has been attributed to neurogenesis impairment during fetal brain development. Consistently with explicit memory alterations observed in children with DS, fetuses with DS exhibit neurogenesis impairment in the hippocampus, a key region involved in memory formation and consolidation. Recent evidence suggests that the subiculum plays a unique role in memory retrieval, a process that is also altered in DS. While much attention has been devoted to the hippocampus, there is a striking lack of information regarding the subiculum of individuals with DS and DS models. In order to fill this gap, in the current study, we examined the subiculum of fetuses with DS and of the Ts65Dn mouse model of DS. We found that in fetuses with DS (gestational week: 17-21), the subiculum had a reduced thickness, a reduced cell density, a reduced density of progenitor cells in the ventricular zone, a reduced percentage of neurons, and an increased percentage of astrocytes and of cells immunopositive for calretinin-a protein expressed by inhibitory interneurons. Similarly to fetuses with DS, the subiculum of neonate Ts65Dn mice was reduced in size, had a reduced number of neurons and a reduced number of proliferating cells. Results suggest that the developmental defects in the subiculum of fetuses with DS may underlie impairment in recall memory and possibly other functions played by the subiculum. The finding that the subiculum of the Ts65Dn mouse exhibits neuroanatomical defects resembling those seen in fetuses with DS further validates the use of this model for preclinical studies., (© 2018 International Society of Neuropathology.)

Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17-21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR-positive vs. CR-negative cells was greater than in euploid fetuses, both in the FG (177%) and ITG (161%). An increased ratio of CR-positive vs. CR-negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS., (© 2018 International Society of Neuropathology.)