Abnormal development of the inferior temporal region in fetuses with Down syndrome

Abstract

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 (+77%) and ITG (+61%). 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.

New approaches to studying early brain development in Down syndrome

“…These studies suggest that the known reductions in brain size (2D and 3D measures) and weight emerge during the fetal and newborn period . During the second trimester, reduced cellular proliferation and increased cell death reflect the observation that fewer neurons are seen in the neocortex, hippocampus, and cerebellum . Fewer neurons in the ventricular zone and subventricular zone further suggest an underproduction of excitatory neurons, leading to enhanced inhibitory neural activity that may underlie some of the cognitive deficits observed in Down syndrome .…”

“…34,35 During the second trimester, reduced cellular proliferation and increased cell death reflect the observation that fewer neurons are seen in the neocortex, hippocampus, and cerebellum. [36][37][38][39][40] Fewer neurons in the ventricular zone and subventricular zone further suggest an underproduction of excitatory neurons, leading to enhanced inhibitory neural activity that may underlie some of the cognitive deficits observed in Down syndrome. 37,40,41 A reduction in serotonin levels has also been described in fetal brains with Down syndrome.…”

Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome

“…Histological analyses found reduced cortical plate thickness, less discrete laminar structures, as well as alterations in laminar cell density in the supra temporal gyrus (Golden and Hyman 1994). Such changes appeared to be caused by decreased neurogenesis (Guidi et al 2008;Guidi et al 2018) including decreased cortical interneurons (Bhattacharyya et al 2009) and hippocampal neurons (Guidi et al 2008). In addition, decreased cells with glial lineages have been documented (Kanaumi et al 2013).…”

“…Most data are derived from fetopsy and not from the observation of living fetuses. Fetopsies have found decreased volumes in the temporal lobes and cerebellum, likely associated with decreased neurogenesis, altered neuronal differentiation, and apoptosis in broad regions of fetal brain (Golden and Hyman 1994;Guihard-Costa et al 2006;Guidi et al 2008;Bhattacharyya et al 2009;Kanaumi et al 2013;Guidi et al 2018). These findings suggest that the brain pathology in DS originates in utero and continues over the lifespan.…”

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

“…Data suggest that primarily small, granular, presumably GABAergic neurons in layers II and IV of the cortex are affected. 239 Additional hypocellularity has been reported in other brain regions, including the hippocampus and cerebellum, [241][242][243] during development, suggesting a general defect in neurogenesis in DS. 244 Impaired neurogenesis has been reported in DS mouse models 241,245-247 but does not consistently decrease the number of neurons in the mouse brain to recapitulate the reduced number of neurons in the brains of DSaffected individuals.…”