CDKL5 deficiency in adult glutamatergic neurons alters synaptic activity and causes spontaneous seizures via TrkB signaling

CDKL5 deficiency disorder (CDD) is a severe epileptic encephalopathy resulting from pathological mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. Despite significant progress in understanding the neuronal function of CDKL5, the molecular mechanisms underlying CDD-associated epileptogenesis are unknown. Here, we report that acute ablation of CDKL5 from adult forebrain glutamatergic neurons leads to elevated neural network activity in the dentate gyrus and the occurrence of early-onset spontaneous seizures via tropomyosin-related kinase B (TrkB) signaling. We observe increased expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of its receptor TrkB in the hippocampus of Cdkl5-deficient mice prior to the onset of behavioral seizures. Moreover, reducing TrkB signaling in these mice rescues the altered synaptic activity and suppresses recurrent seizures. These results suggest that TrkB signaling mediates epileptogenesis in a mouse model of CDD and that targeting this pathway might be effective for treating epilepsy in patients affected by CDKL5 mutations. [Display omitted] •Loss of Cdkl5 in adult mouse glutamatergic neurons results in robust seizures•BDNF-TrkB signaling is enhanced in Cdkl5-deficient mice•Altered synaptic activity resulting from Cdkl5 deficiency is mediated by TrkB signaling•Inhibition of TrkB signaling suppresses seizures caused by loss of Cdkl5 activity Zhu et al. show that deletion of Cdkl5 in the adult mouse brain in a glutamatergic neuron-specific manner induces robust early-onset seizures. BDNF-TrkB signaling is enhanced in these mutant mice. Inhibition of TrkB activity rescues the altered synaptic activity and suppresses seizures caused by loss of Cdkl5.