Early Appearance of Dendritic Alterations in Neocortical Pyramidal Neurons of the Ts65Dn Model of Down Syndrome

Abstract

Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the lifespan have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice the distalmost apical branches were missing or reduced in number but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice, and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.

The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives

“…It has been suggested that cognition defects in different types of ID may be underpinned by alterations of different dendritic domains ( Granato and Merighi, 2022 ). In this connection it is interesting to note that dendritic branching defects in Ts65Dn pups mainly involve the basal domain shortly after birth (postnatal day 2) and the apical domain slightly later (postnatal day 8) suggesting a relationship between age, affected dendritic compartment ( Uguagliati et al, 2022 ) and, possibly, cognitive impairment in DS.…”

“…Recent evidence shows that granule neurons of Ts65Dn mice already exhibit dendritic hypotrophy and spine shape (but not density) alterations at postnatal day 8 ( Uguagliati et al, 2021 ). The presence of dendritic branching defects has been additionally found in neocortical pyramidal neurons of Ts65Dn pups aged 2 days ( Uguagliati et al, 2022 ). Taken together the latter two studies are in line with the early presence of dendritic alterations seen in infants with DS.…”

“…In the cerebellum, granule cell production begins at E12.5 and E15.5 and is accomplished by the second postnatal week ( Sillitoe and Joyner, 2007 ; Sudarov and Joyner, 2007 ). The basal and apical arbors of cortical pyramidal neurons appear at postnatal day 2 and attain maturation within the third week ( Meller et al, 1969 ; Uguagliati et al, 2022 ). Cortical spinogenesis begins at postnatal days 6–9 and is completed by the third postnatal week ( Meller et al, 1969 ; Uguagliati et al, 2022 ).…”

“…The basal and apical arbors of cortical pyramidal neurons appear at postnatal day 2 and attain maturation within the third week ( Meller et al, 1969 ; Uguagliati et al, 2022 ). Cortical spinogenesis begins at postnatal days 6–9 and is completed by the third postnatal week ( Meller et al, 1969 ; Uguagliati et al, 2022 ).…”

Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?

“…In mice, an apical and basal dendritic arbor is already detectable in neocortical pyramidal neurons at postnatal day (PD) 2, but the apical arbor is less well developed than the basal arbor [ 133 ]. Similarly, in rats, the basal and apical dendritic arbor of CA1 pyramidal neurons has a different time course; the number of basal dendrites is already established at the age of 5 days, while the lateral and terminal branches of the apical arbor emerge later [ 134 ].…”