NeuroPSI – Paris-Saclay University

Brain development in a mouse model of Coffin-Lowry syndrome associated with intellectual disability during postnatal period

Abstract
Intellectual disabilities (ID) affect 1% of the population and are associated with alterations in brain development during the embryonic and/or postnatal period. Among inherited IDs, Coffin-Lowry syndrome (CLS) is a rare disease characterized by moderate to severe ID associated with physical and neurological abnormalities. CLS is caused by mutations in the RPS6KA3 gene that lead to an absent or truncated RSK2 protein kinase. My project aims to characterize the role of RSK2 in brain and cognitive development during the postnatal period. Behavioural phenotype analyses showed that CLS-mouse model (Rsk2-KO) exhibits transient delays in the development of sensory, motor, proprioceptive and cognitive systems from an early age. Longitudinal MRI analyses showed a delayed brain development in Rsk2-KO mice from the second postnatal week, which is spontaneously compensated in adulthood. However, the volumes of brain structures such as hippocampus and cerebellum remained particularly reduced. Using immunohistochemical and biochemical techniques, we demonstrated several cellular and molecular alterations in these two structures, such as a defect in the dendritic growth of pyramidal cells in the hippocampus and Purkinje cells in the cerebellum, alterations in postnatal neurogenesis, and a dysregulation of some actors of the MAP Kinase signaling pathway. Together, these results revealed that the absence of RSK2 leads to a delay in the maturation of brain structures during postnatal development, a critical period for the development of neuronal networks and cognitive processes. This maturation delay could be responsible, at least in part, for the apparition of the cognitive deficits observed in juvenile mice.

Jury Members

• • Sylvie GRANON, Président (NeuroPSI, Saclay)
  • Hervé MOINE, Reviewer (IGBMC, Strasbourg)
  • Emilie PACARY, Reviewer (NeuroCampus, Bordeaux)
  • Corentin Le MAGUERESSE, Jury member (IFM, Paris)
  • Julie Le MERRER, Jury member (iBrain, Tours)

and

• Roseline POIRIER & Cyrille VAILLEND (Institut NeuroPSI, Saclay)