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ABSTRACT

CDKL5 controls nociception in human neurons and murine models of CDKL5 deficiency disorder via CaMKII-dependent mechanisms. A painful mechanism in CDD CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by mutations in the cyclin-dependent–like kinase 5 (CDKL5) gene. Now, La Montanara et al. found that patients with CDD, in addition to the known symptoms, had altered pain sensitivity. Mechanistically, the authors found that CDKL5 is expressed in sensory neurons and regulates CaMKII-dependent TRPV1 signaling, thus affecting pain perception. In rodents, Cdkl5 deletion in sensory neurons resulted in reduced pain sensitivity. The results suggest that restoration of pain perception should be considered when developing therapies for treating CDD. Cyclin-dependent–like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)–derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)–dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS–derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

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