Normalization of network activity in an epilepsy model with a constitutively active GABBR2 variant

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• GABAB receptors (GBRs), composed of GB1 and GB2 subunits, mediate neuronal inhibition.
• Monoallelic GABBR2 variants (p.A567T, p.S695I, p.I705N) are linked to epileptic encephalopathy and Rett-like disorders.
• These phenotypes overlap with GABBR1 loss-of-function variants, suggesting complex GBR dysregulation.

Purpose of the Study:

• To investigate the functional impact of GABBR2 variants on GBR activity and neuronal function.
• To explore the therapeutic potential of modulating GBRs in a mouse model of GABBR2-associated disorders.

Main Methods:

• Heterologous cell expression and luciferase reporter assays to assess GBR pharmacological profiles.
• Generation and analysis of Gabbr2I704N/+ mice using EEG, electrophysiology, and proteomics.
• In vivo electrophysiological recordings and pharmacological interventions.

Main Results:

• GABBR2 variants exhibited significant constitutive GBR activity (gain-of-function) in heterologous cells.
• Gabbr2I704N/+ mice showed δ-band EEG abnormalities, increased constitutive GBR activity, and reduced agonist responsiveness.
• Proteomic analysis revealed downregulation of GBR subunits and signaling proteins, suggesting an adaptive response.
• Pharmacological treatment with a GBR positive allosteric modulator normalized network activity.

Conclusions:

• Constitutively active GABBR2 variants lead to adaptive GBR downregulation, contributing to neurological phenotypes.
• Positive allosteric modulators represent a potential therapeutic strategy for GABBR2-related disorders.