Defective synaptic contacts underlie neurodevelopmental disorders

A way by which the protein kinase CDKL5 promotes dendritic spine growth and synaptic contacts during neuronal development is reported in a paper in Nature Cell Biology this week. The work outlines how depleted levels of this molecule disrupts neuronal activity and sheds light on how human mutations associated with neurodevelopmental disorders affect neuronal function.

In humans, mutations in the gene encoding CDKL5 were previously linked to a particular form of Rett syndrome that manifests itself through neurodevelopmental disorders, early-onset epilepsy and autism. Vania Broccoli and colleagues found that CDKL5 localizes to the zone of synaptic contacts in the mouse brain. They show that depleting CDKL5 in human cells and in a mouse model prevents the normal development of synaptic contacts and normal excitatory activity of neurons. They find, both in the mouse and human cells, that CDKL5 modifies the cell adhesion molecule NGL-1 by phosphorylation - which switches enzymes on and off, thereby altering their function and activity - in order to promote its interaction with proteins essential for the development of synaptic contacts.

The authors also note that pluripotent cells from people with CDKL5 mutations exhibit lower levels of NGL-1 phosphorylation and defects in synapse formation, similarly to mouse neurons in which CDKL5 was silenced.