Discovery of a new mechanism involving GABA-B receptors and the protein AJAP-1 in the localization of these receptors in the brain (Bettler Lab)
The DBM congratulates the Bettler Lab for their recent paper accepted by Science Advances. The authors have uncovered a novel mechanism involving GABA-B receptors and the protein AJAP-1, which maintains the receptors' placement in the brain. GABA is a neurotransmitter that inhibits neuronal activity, and while AJAP-1 was previously linked to brain disorders, its exact role was unclear. The study, conducted with clinicians in the U.S. and Europe, examined patients with developmental and neurological issues like intellectual disability, autism, and epilepsy. They discovered that spontaneous mutations in the AJAP1 gene disrupted the interaction between AJAP-1 and GABA-B receptors, causing the GABA receptors to be lost from synapses. This loss leads to a lack of control over neuronal activity in the brain, explaining the severe symptoms observed in patients.
Neurotransmitter receptors typically function within multi-protein complexes, but the specific roles of associated proteins are often unclear. The study conducted by the Bettler lab and clinicians worldwide has identified a widely expressed protein in the brain that trans-synaptically recruits GABA receptors to synapses. They show that monoallelic de novo mutations in this protein disrupt its function, explaining the severe neurodevelopmental, neurological, and psychiatric symptoms in affected individuals.
GABA, the main inhibitory neurotransmitter in the brain, signals through two types of receptors: GABA-A and GABA-B receptors. Recent genetic studies have causally linked loss-of-function variants in the GABA-B receptor gene GABBR1 to a range of clinical symptoms, including motor delay, intellectual disability, autism, attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), sleep disorders, muscular hypotonia, and epilepsy. These disorders are thought to result from an elevated excitation-inhibition ratio in neuronal networks due to uncontrolled release of excitatory neurotransmitters, ultimately leading to seizures.
In earlier proteomic studies, the researchers identified adherens-junction-associated protein 1 (AJAP1) as a component of GABA-B receptor complexes in the brain. Although AJAP1 is widely expressed in neurons, its role was previously unknown. In collaboration with clinical scientists in the US and Europe, the Bettler lab identified several individuals with potentially pathogenic monoallelic variants in the AJAP1 gene. These individuals presented with epilepsy, neurodevelopmental problems, and intellectual disability. Notably, the clinical features closely overlap with those observed in individuals with pathogenic loss-of-function variants in the GABBR1 gene, suggesting that AJAP1 variants impair GABA-B receptor function.
In their current study, they elucidated how AJAP1 influences GABA-B receptor functioning. Through cellular assays, they discovered that AJAP1 acts as a postsynaptic protein, enabling the trans-synaptic recruitment of GABA-B receptors to presynaptic sites. To investigate synaptic deficits caused by potentially pathogenic monoallelic AJAP1 variants, they engineered mice with human variants inserted into the corresponding position in the mouse gene. Their analysis revealed that variant AJAP1 proteins failed to bind to GABA-B receptors, thus hindering their recruitment to presynaptic sites. Electrophysiological experiments further confirmed a subsequent deficiency in presynaptic GABA-B receptor function, leading to the uncontrolled release of excitatory neurotransmitters. Their findings offer a mechanistic understanding of how deficiencies in both AJAP1 and GABBR1 contribute to similar synaptic dysfunctions and clinical features and underscores the significance of comprehending native protein complexes for insights into biological processes and disease mechanisms.
Original Publication: https://www.science.org/doi/10.1126/sciadv.adk5462