Cdkl5, or cyclin-dependent kinase-like 5, is a serine-threonine kinase encoded by an X-linked gene highly expressed in the developing brain. It regulates key phosphorylation events crucial for the development of the brain's complex neuronal network. Cdkl5 is involved in pathways related to axon outgrowth, dendritic morphogenesis, and synapse formation [1,3]. Mouse models deficient in Cdkl5 have been valuable for in-vivo functional studies.

In Cdkl5-deficient mouse models, acute ablation of Cdkl5 from adult forebrain glutamatergic neurons leads to elevated neural network activity in the dentate gyrus and early-onset spontaneous seizures via tropomyosin-related kinase B (TrkB) signaling. There is increased expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of TrkB in the hippocampus prior to behavioral seizures, and reducing TrkB signaling can rescue the synaptic activity and suppress seizures [2]. Also, deletion of Cdkl5 in mice reduces virophagy of neurotropic viruses like Sindbis virus, increasing viral antigen accumulation, neuronal cell death, and lethality after infection. Mechanistically, Cdkl5 binds and phosphorylates the autophagy receptor p62 to promote its interaction with viral capsid aggregates [4].

In conclusion, Cdkl5 is essential for normal brain development and function, regulating synaptic activity and autophagy-related antiviral responses. Studies using Cdkl5-deficient mouse models have revealed its role in epileptogenesis and antiviral immunity, providing insights into the pathogenesis of CDKL5 deficiency disorder and potential therapeutic targets for associated diseases [2,4].