Synaptic and Glial Mechanisms of GABA-A Receptor Dysfunction in Epilepsy
Speaker: Dr Nela Durisic
Queensland Brain Institute
University of Queensland
Synaptic and Glial Mechanisms of GABA-A Receptor Dysfunction in Epilepsy
Abstract: The GABA-A receptor (GABAAR) is a central mediator of both phasic and tonic inhibition in the brain, and pathogenic variants in its subunits are increasingly recognised as important causes of severe paediatric epilepsies. In this seminar, I will present new data examining how distinct receptor variants differentially alter inhibitory signalling, receptor surface expression, and nanoscale organisation at neuronal synapses and in astrocytes.
By dissecting the underlying mechanisms, we distinguish reduced inhibition resulting from impaired receptor trafficking and decreased surface stability from dysfunction caused by altered channel conductance, and relate these molecular mechanisms to clinical severity. Notably, variants that enhance receptor activity can paradoxically be associated with particularly severe phenotypes, and I will present at least one explanation for this. I will also show that profound receptor dysfunction affects excitatory synapse maintenance and that, in cortical astrocytes, epilepsy-associated variants drive context-dependent changes in receptor organisation influenced by neuron–glia interactions.
Together, these findings highlight how altered localisation of GABAARs in neurons and astrocytes destabilises excitation–inhibition balance, leading to inhibitory failure in cortical networks and contributing to diverse epileptic phenotypes. Finally, I will discuss a potential therapeutic avenue leveraging these mechanistic insights that involves drug repurposing.
About Neuroscience Seminars
Neuroscience seminars at the QBI play a major role in the advancement of neuroscience in the Asia-Pacific region. The primary goal of these seminars is to promote excellence in neuroscience through the exchange of ideas, establishing new collaborations and augmenting partnerships already in place.
Seminars in the QBI Auditorium on Level 7 are held on Wednesdays at 12-1pm, which are sometimes simulcast on Zoom (with approval from the speaker). We also occassionally hold seminars from international speakers via Zoom. The days and times of these seminars will vary depending on the time zone of the speaker. Please see each seminar listed below for details.
