RESCHEDULED Neurobiology Virtual Seminar

June 23, 2020 - 12:00pm to 1:00pm
Wolfgang Liedtke, MD, PhD

Wolfgang Liedtke will present "From the junkyard of cancer drugs to repair of defective inhibitory neurotransmission: Re-normalizing injury-associated elevated neuronal chloride by enhancing gene expression of KCC2" on Zoom.
Email ladonna.huseman@duke.edu for connection details.

ABSTRACT: Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride ion concentrations in neurons. This basic ionic homeostatic mechanism relies on expression and function of KCC2, a neuroprotective ionic transporter that extrudes neuronal chloride. Importantly, no other transporter can rescue KCC2 deficit, and attenuated expression of KCC2 is a hallmark of circuit malfunction in chronic pain, epilepsy, neuro-degeneration, neuro-trauma, and other neuro-psychiatric illnesses.
Based on the hypothesis that restoration of Kcc2 expression levels and resulting improvement of GABA evoked chloride reversal potentials in pain relay neurons will relieve pathologic pain, we have conducted a screen for small molecules that increase Kcc2 transcription using primary mouse cortical neurons harboring a Kcc2 promoter luciferase reporter. The screen started with 1057 growth regulating compounds from collections curated by the National Cancer Institute, based on the idea that many of them likely impact transcriptional and epigenetic mechanisms, and many of them have already been fed into a translational pipeline.