Down syndrome hippocampal defects improved in a mouse model
In a recent work published in Neurobiology of disease, the research groups lead by Mara Dierssen at the CRG and Cristina Fillat, now at the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) have joined efforts to find a potential therapeutic target for Down Syndrome (mice).
Down Syndrome (DS), caused by the trisomy of human chromosome 21 (HSA21), is the most common chromosome abnormality in humans. It is typically associated with a delay in cognitive ability, with an average IQ of around 50 in young adults compared with 100 in adults without the condition, as well as with physical growth and a particular set of facial characteristics.
The Ts65Dn mouse is a genetic model for DS with a trisomy of the homologous chromosome in mice. In this model, overexpression of HSA21 homologous genes has been associated with strong visuo-spatial cognitive alterations, ascribed to hippocampal dysfunction. One of these genes is Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), a candidate gene for DS which seems to play a significant role in a signaling pathway regulating cell proliferation and which may be involved in brain development.
Dierssen, Fillat and colleagues decided to study whether the normalization of the expression levels of Dyrk1A – that is, reducing its expression, which in these mice is double than normal – might correct hippocampal defects in Ts65Dn mice.
They injected adeno-associated viruses containing a short hairpin RNA against Dyrk1A and a Luciferase reporter gene in the hippocampus of 2 months-old Ts65Dn mice. After checking that the injected hippocampi were efficiently transduced (via bioluminescence in vivo imaging, luciferase activity quantification and immunohistochemical analysis) and that the Dyrk1A expression had indeed been normalized at the molecular level, the researchers compared electrophysiological recordings of hippocampal slices from the Ts65Dn injected mice with those from mice injected with an AAV2/1 control virus.
The mice with normalized Dyrk1A levels displayed attenuation of the synaptic plasticity defects of trisomic mice. They also showed partial improvement in their hippocampal-dependent search strategy, as seen in the Morris water maze task – although long-term consolidation of the task was not achieved.
As the authors conclude, these results show Dyrk1A as a critical player in the pathophysiology of DS and define Dyrk1A as a therapeutic target in adult trisomic mice.
Altafaj X, Martín E, Ortiz-Abalia J, Valderrama A, Lao-Peregrin C, Dierssen M, Fillat C. Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2012 Dec 4;