Developmental and epileptic encephalopathy: presynaptic hyperexcitability reversed by positive allosteric modulation of GABA receptors

What are the molecular mechanism underlying GABA_B receptor variant developmental and epileptic encephalopathy and how can these be reversed?

To date, only a handful GABA_B receptor GABA_B variants are known are known to cause developmental and epileptic encephalopathy.

Here, we studied the biophysical, trafficking and functional profiles of three of these variants. By studing these receptors in neurons for the first time, we show that these variants fail to express on the cell surface of neurons and for at least one of the variants result in presynaptic hyperexcitability.

Our results show the importance of studying neuronal receptors in nervous tissue and shows that correction of presynaptic hyperexcitability by positive allosteric modulation of GABA_B receptors could be a viable therapeutic strategy for GABA_B receptor epilepsies.

GABA_B variants fail to express on neuronal plasma membrane even though they express in cell lines

By expressing three GABA_B receptor variants (G693W, I695N and S705I) for the first time in hippocampal neurons, we reveal a complete absence of variant expression in neurons despite these receptors expressing well in mammalian cell lines such as HEK-293 cells here and in previous studies.

Therefore lack of neural expression will lead to haploinsufficiency and neural hyperexcitability that could underlie seizures.

Acting in a dominant negative fashion, S695I dampens endogenous GABA_B receptor function

Using whole cell electrophysiology, we report that expression of S695I reduces GABA_B receptor specific agonist baclofen activated K⁺ currents in hippocampal neurons

Presynaptic hyperactivity due to expression GABA_B receptor variant S695I

Using Ca²⁺ imaging of GCaMP6f fused to synaptophysin we report presynaptic hyperexcitability ensues due to expression of S695I

Correction of presynaptic hyperexcitability by positive allosteric modulation of GABA_Breceptors

The presynaptic hyperexcitability can be reversed by the application of a GABA_B receptor positive allosteric modulator demonstrating the therapeutic potential of this approach for treatment of GABA_B receptor epilepsy.

For more details please visit the publication:

M Minere, M Mortensen, V Dorovykh, G Warnes, D Nizetic, TG Smart* & SB Hannan* (2024). Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABA_BR epilepsy variant. Brain, awae232

*corresponding authors