Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• GABAergic circuits are vital for brain network synchronization and function.
• Defects in GABAergic circuitry are implicated in neuropsychiatric disorders like bipolar disorder, schizophrenia, and autism.
• Ankyrin-G stabilizes GABA receptors at synapses, interacting with GABARAP in cultured neurons.

Purpose of the Study:

• To investigate the in vivo role of the ankyrin-G/GABARAP interaction in regulating GABAergic circuitry.
• To understand the functional consequences of disrupting this interaction using a novel mouse model.

Main Methods:

• Generation of a knock-in mouse model (Ank3 W1989R) with a disrupted ankyrin-G/GABARAP interaction.
• Analysis of GABAergic synapse density, neuronal excitability, and network synchronization in mutant mice.
• Examination of structural changes in pyramidal cells and genetic analysis of a human family.

Main Results:

• Ank3 W1989R mice showed a significant reduction in forebrain GABAergic synapses.
• Pyramidal cells in mutant mice exhibited hyperexcitability and disrupted network synchronization.
• Compensatory changes were observed in pyramidal cell dendritic spines and axon initial segments.
• The ANK3 W1989R variant was identified in a family with bipolar disorder.

Conclusions:

• The ankyrin-G/GABARAP interaction is essential for regulating forebrain GABAergic circuitry in vivo.
• Disruption of this interaction leads to hyperexcitability and network dysfunction.
• Loss-of-function ANK3 variants may contribute to the pathophysiology of human neuropsychiatric diseases, including bipolar disorder.