Neuronal Cell-Intrinsic Defects in Mouse Models of Down Syndrome

Down Syndrome (DS) is a disease caused by the triplication of Human chromosome 21 and it is recognised as the leading genetic cause of intellectual disability. Cerebral neocortex is one of the most affected brain structures and qualitative and quantitative defects such as the reduction in dendritic arborizations and a decreased number of synaptic contacts have been documented in both DS patients and mouse models. However, whether these alterations are caused by cell autonomous events or by abnormal multicellular circuitry is still unknown. In this work, we investigated the possible cellular basis of cortical structure alterations of DS brain by culturing cortical neurons obtained from two mouse models: Ts65Dn and Ts2Cje. No significant impairment in the establishment of neuronal polarity, axon outgrowth and dendritogenesis was observed, demonstrating that early stages of neuronal development are unaffected by the imbalanced genetic dosage. Conversely, trisomic neurons in culture show a compromised capability to grow and mature dendritic spines compared to euploid cells, demonstrated by a reduction of spine density and by a significant decrease in number of long neck and mushroom spines, which carry the largest and most mature excitatory synapses. Our results suggest that synaptic defects seen in trisomic neurons are likely due to cell-intrinsic mechanisms, even though cell-extrinsic factors may exacerbate the phenomenon. Additionally, we described more in depth the stages of neuronal development in the Ts2Cje mouse model, further validating the novel, but more sustainable line which could be now used as a standard model for the study of DS.