Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome

Abstract

Down syndrome is the most common genetic cause of intellectual disability and occurs due to the trisomy of human chromosome 21. Adolescent and adult brains from humans with Down syndrome exhibit various neurological phenotypes including a reduction in the size of the corpus callosum, hippocampal commissure and anterior commissure. However, it is unclear when and how these interhemispheric connectivity defects arise. Using the Ts65Dn mouse model of Down syndrome, we examined interhemispheric connectivity in postnatal day 0 (P0) Ts65Dn mouse brains. We find that there is no change in the volume of the corpus callosum or anterior commissure in P0 Ts65Dn mice. However, the volume of the hippocampal commissure is significantly reduced in P0 Ts65Dn mice, and this may contribute to the impaired learning and memory phenotype of this disorder. Interhemispheric connectivity defects that arise during development may be due to disrupted axon growth. In line with this, we find that developing hippocampal neurons display reduced axon length in vitro, as compared to neurons from their euploid littermates. This study is the first to report the presence of defective interhemispheric connectivity at the time of birth in Ts65Dn mice, providing evidence that early therapeutic intervention may be an effective time window for the treatment of Down syndrome.3

Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits

“…In Ts65Dn mice, delays in growth of the neocortex and hippocampus have been noted with the first changes seen on E14.5 (Chakrabarti et al, 2007). However, like in people with DS, the most significant alterations have been observed in postnatal (P0-P16) development (Lorenzi and Reeves, 2006;Contestabile et al, 2007;Lysenko et al, 2018;Jain et al, 2020;Uguagliati et al, 2022). These postnatal changes were accompanied by significant delays in achieving developmental motor and sensory milestones (Holtzman et al, 1996;Toso et al, 2008;Olmos-Serrano et al, 2016).…”