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Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant

Summary

Researchers studied three genetic mutations in GABA_B receptors that cause severe epilepsy and developmental problems in children. They found that these mutations prevent the receptors from reaching the cell surface and cause excessive calcium buildup in nerve terminals, leading to overexcitability. Using a special drug compound that enhances GABA_B receptor activity, the team was able to reverse these harmful effects, offering a potential new treatment strategy for affected patients.

Background

GABA_B receptors are key inhibitory neurotransmitter receptors that regulate neuronal excitability. Recent studies have identified three variants (G693W, S695I, I705N) in the GABBR2 gene encoding GABA_BR2 subunits in individuals with severe developmental epileptic encephalopathy and intellectual disability, but the underlying mechanisms remain unclear.

Objective

To characterize the biophysical, molecular trafficking, and functional profiles of three GABA_BR2 epilepsy variants (G693W, S695I, I705N) and determine whether positive allosteric modulation can rescue the synaptic deficits caused by these mutations.

Results

All three variants impaired neuronal cell surface expression of GABA_BRs and reduced signaling efficacy. Notably, S695I elevated presynaptic Ca2+ signaling, indicating increased presynaptic excitability. Positive allosteric modulation with rac-BHFF effectively normalized presynaptic Ca2+ transients and reversed the deleterious effects of S695I.

Conclusion

The study reveals that GABA_BR variants cause neurodevelopmental disease through impaired cell surface expression and elevated presynaptic excitability. Positive allosteric modulation represents a promising therapeutic approach for correcting these deficits and treating epilepsy associated with these variants.
  • Published in:Brain,
  • Study Type:Experimental Research Study,
  • Source: PMID: 39028675, DOI: 10.1093/brain/awae232
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