CDKL5 Deficiency Augments Inhibitory Input into the Dentate Gyrus That Can Be Reversed by Deep Brain Stimulation.

Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency, a neurodevelopmental disorder characterized by early epileptic seizures, intellectual disability, and autistic behaviors. Although loss of CDKL5 affects a number of molecular pathways, very little has been discovered about the physiological effects of these changes on the neural circuitry. We therefore studied synaptic plasticity and local circuit activity in the dentate gyrus of both and mutant mice. We found that CDKL5 haploinsufficiency in both male and female mice impairs hippocampus-dependent learning and memory in multiple tasks. , loss of CDKL5 reduced LTP of the perforant path to the dentate gyrus and augmented feedforward inhibition in this pathway; experiments confirmed that excitatory/inhibitory input into the dentate gyrus is skewed toward inhibition. Injecting the GABAergic antagonist gabazine into the dentate improved contextual fear memory in mice. Finally, chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in mice. These results indicate that CDKL5 is important for maintaining proper dentate excitatory/inhibitory balance, with consequences for hippocampal memory. Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Although CDKL5 deficiency has been found to affect a number of molecular pathways, little is known about its physiological effects on the neural circuitry. We find that CDKL5 loss reduces hippocampal synaptic plasticity and augments feedforward inhibition in the perforant path to the dentate gyrus in mutant mice. Chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in mice, as it had previously done with Rett syndrome mice, suggesting that such stimulation may be useful for other neurodevelopmental disorders.