Description:

Please join the Department of Pharmacology for a Works-in-Progress presentations

Sam Kang, Graduate Student in the Laboratory of Dr. Jennifer Kearney

"High-Throughput Characterization of KCNB1 Variants Associated with Infantile Epilepsy"

Epilepsy is a common neurological disease, yet our understanding on the neurophysiology of epilepsy is incomplete. A significant portion of human epilepsy is caused by genetic factors which cause malfunctioning of ion channels that control our brain network. Mutations in the KCNB1 gene have been identified in epileptic patients who suffer infantile seizures. KCNB1 encodes voltage-gated K+ channel, and accumulating evidence suggests that not all KCNB1 mutations are the equivalent. Each KCNB1 mutation may have a differential effect in the brain at cellular and molecular level. We investigated how a series of KCNB1 variants affects channel protein function and expression using high-throughput electrophysiology and flow cytometry. The results of this study will allow us to gain valuable insights for developing animal models of KCNB1-related epilepsy and novel therapies for patients with KCNB1 mutations. 

Jiejie Wang, Ph.D., Postdoctoral Fellow in the Laboratory of Dr. Antonio Sanz-Clemente

"BDNF-Dependent Regulation of Glutamate Receptor Trafficking During Development: Implications in Rett Syndrome"

NMDA Receptors (NMDARs) are glutamate-gated ion channels that control synaptic plasticity, contribute to synaptic neurotransmission and are critically involved in developmental processes such as spine growth, synaptogenesis, and synaptic remodeling and maturation. We have identified a novel molecular mechanism that dynamically regulates NMDAR trafficking at early developmental stages: a BNDF-dependent, PKC-mediated phosphorylation of the intracellular tail (on S1323) of the GluN2B subunit of NMDARs. This phosphorylation is prominent at early postnatal days in rodents, controls the surface expression of NMDARs by impairing their recycling and, as a consequence, affects the population of AMPA receptors expressed at the plasma membrane. Alterations in NMDAR localization and/or function have been observed in neurodevelopmental disorders associated with intellectual disability. Patients and animal models of Rett syndrome, the leading cause of mental retardation in females, are characterized by a strong decrease in BDNF levels. We have, therefore, investigated a possible dysregulation of GluN2B S1323 phosphorylation in RTT. Our longitudinal studies using a mouse model of RTT have identified not only an alteration in GluN2B S1323 phosphorylation but also a distinct, developmentally dependent dysregulation in the expression of different AMPAR subunits in RTT. Our data indicate a potential molecular link between the aberrant GluN2B S1323 phosphorylation-dependent trafficking of NMDAR and the abnormal neuronal connectivity observed in RTT.