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Description

Down syndrome (DS) is a common genetic developmental disorder characterized by the trisomy of chromosome 21 (Hsa21). All individuals with DS have some kind of intellectual disability, associated with dysfunction in cognition-related structures, including the frontal cortex. Studies have examined developmental changes in the frontal cortex during prenatal stages in

Down syndrome (DS) is a common genetic developmental disorder characterized by the trisomy of chromosome 21 (Hsa21). All individuals with DS have some kind of intellectual disability, associated with dysfunction in cognition-related structures, including the frontal cortex. Studies have examined developmental changes in the frontal cortex during prenatal stages in DS, however little is known about cortical lamination and neuronal differentiation in postnatal periods in this neurodevelopmental disorder. Therefore, we examined the quantitative and qualitative distribution of neuronal profiles containing the neuronal migration protein doublecortin (DCX), the non-phosphorylated high-molecular-weight neurofilament SMI-32, the calcium-binding proteins calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as human β-amyloid and APP (6E10), Aβ1-42, and phospho-tau (CP-13) in the supragranular (SG, II/III) and infragranular (IG, V/VI) layers in the DS postnatal frontal cortex compared to neurotypically developing (NTD) controls from ages 28 weeks to 196.4 weeks using immunohistochemistry. Furthermore, cortical lamination was evaluated using thionin, a Nissl stain. We found DCX-immunoreactive (-ir) cells in both the SG and IG layers in younger cases, but not in the oldest cases in both groups. Strong expression of SMI-32 immunoreactivity was observed in pyramidal cells in layers III and V in the oldest cases in both groups, however SMI-32-ir cells appeared much earlier in NTD compared to DS. We found small and fusiform Calb-ir cells in the younger cases (28 to 44 weeks), while in the oldest cases, Calb immunoreactivity was also found in pyramidal cells. Calr-ir cells appeared earlier in DS at 32 weeks compared to NTD at 44 weeks, however both groups showed large bipolar fusiform-shaped Calr-ir cells in the oldest cases. Diffuse APP/Aβ-ir plaque-like accumulations were found in the frontal cortex grey and white matter at all ages, but no Aβ1-42 immunoreactivity was detected in any case. Furthermore, neuropil (but not cellular) granular CP-13 immunostaining was seen in layer I only at 41 weeks NTD and 33 weeks DS. Cell counts show a significantly higher cell number in SG compared to IG for all the neuronal markers in both groups, except in Calb and SMI-32. In NTD, age and brain weight showed the strongest correlations with all cellular counts, except in thionin where DS had a stronger negative correlation with age and brain weight compared to NTD. In addition, height and body weight showed a strong negative correlation in NTD with the migration and neurogenesis marker DCX. These findings suggest that trisomy 21 affects the postnatal frontal cortex lamination, neuronal migration<br/>eurogenesis, and differentiation of projection pyramidal cells and interneurons, which contribute to the disruption of the local and projection inhibitory and excitatory circuitries that may underlie the cognitive disabilities in DS.

ContributorsUtagawa, Emma Christina (Author) / Penkrot, Tonya (Thesis director) / Perez, Sylvia (Committee member) / Shafernak, Kristian (Committee member) / College of Health Solutions (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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Description
Down Syndrome (DS), caused by the trisomy 21, is the most common intellectual developmental disorder. Children with DS display deficits in ample memory tasks attributed to alterations in memory-related brain structures, including the hippocampus. Although, many studies in DS focused on development of the brain during prenatal stages, little

Down Syndrome (DS), caused by the trisomy 21, is the most common intellectual developmental disorder. Children with DS display deficits in ample memory tasks attributed to alterations in memory-related brain structures, including the hippocampus. Although, many studies in DS focused on development of the brain during prenatal stages, little is known about the cellular evolution of the hippocampus in postnatal periods in DS. Therefore, here we examined the neurochemical spatiotemporal development of neuronal profiles in pediatric postnatal hippocampus in DS and neurotypical developing (NTD) controls. A quantitative and qualitative neuronal distribution was performed in hippocampal sections containing the proper hippocampus, dentate gyrus (DG) and subiculum obtained at autopsy from 1 day to 3 year-old infants in DS and NTD age-matched controls using antibodies against the non-phosphorylated high-molecular-weight neurofilament, a marker of differentiated neurons (SMI-32), the calcium binding protein calbindin D-28k (CAB), and the migration neuronal marker microtubule-associated protein doublecortin (DCX). In addition, Aβ and phosphorylated tau was also immunohistochemically examined in the hippocampus using 6E10, Aβ1-42 and the phosphorylated CP-13 and AT8 tau antibodies, respectively. We found APP/Aβ immunoreactivity, but not Aβ1-42, in diffuse-like plaques in the hippocampus from 1 day to 3 year old infants and young children in DS and NTD cases. By contrast, phosphorylated fetal tau was not immunodetected in the hippocampus at any age in both groups. SMI-32 immunolabeled neurons were observed in the hilus, CA2 field and subiculum in early postnatal cases in DS and NTD. The number of SMI-32 immunoreactive (ir) granule cells in the DG were significantly decreased in DS compared to NTD. While a strong DCX immunoreactivity was observed in the granule cells of the DG in the hippocampus in both groups at early postnatal stages, a more accelerated reduction was observed in DS. CAB-ir neuronal distribution in the postnatal hippocampus was comparable between the youngest and the oldest infants in NTD and DS. In addition, strong positive correlations were observed between DG-DCX-ir cells numbers and both DG-CAB-ir and DG-SMI-32-ir values as well as negative correlations between the brain weight and DG granule cell-ir numbers for all markers in DS. These findings suggest that neuronal maturation and migration in the hippocampus are compromised in early postnatal stages of the development in DS and may contribute to the intellectual disabilities observed in this group.
ContributorsMoreno, David (Co-author) / Perez, Sylvia E. (Co-author, Thesis director) / Velazquez, Ramon (Thesis director) / Schafernak, Kristian T. (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05