Jianrong Tang

Title : CDKL5 deficiency augments inhibitory input into the dentate gyrus that can be reversed by deep brain stimulation

Abstract:

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 Cdkl5-/y and Cdkl5+/- mutant mice. We found that CDKL5 haploinsufficiency in both male and female mice impairs hippocampus-dependent learning and memory in multiple tasks. In vivo, loss of CDKL5 reduced LTP of the perforant path to the dentate gyrus and augmented feedforward inhibition in this pathway; ex vivo 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 Cdkl5-/y mice. Finally, chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in Cdkl5+/- mice. These results indicate that CDKL5 is important for maintaining proper dentate excitatory/inhibitory balance, with consequences for hippocampal memory.

What will audience learn from your presentation?

• Behavioral testing of learning and memory in mice
• In vivo synaptic plasticity in freely moving mice
• In vivo and ex vivo neural circuit analysis in the hippocampus
• Intracranial drug infusion in mice
• Deep brain stimulation

Biography:

Dr. Tang earned his Ph.D. in Physiology from East China Normal University in 1997 and did postdoctoral training at University of Hamburg and Max-Planck Institute of Psychiatry. He is currently an Associate Professor at Baylor College of Medicine. The Tang lab studies the neuronal- and circuit-level mechanisms that give rise to higher brain functions (e.g., memory and motor). We recently found that deep brain stimulation in the fimbria-fornix rescues hippocampal memory, synaptic plasticity, adult neurogenesis, abnormal circuit activities, and gene expression in mouse models of intellectual disability disorders. Dr. Tang has published 35 papers in SCI journals including Nature, Neuron.