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GABA B receptors (GBRs) are G protein-coupled receptors that mediate the actions of the inhibitory neurotransmitter GABA in the central nervous system. Early pharmacological studies with the GBR agonist baclofen and high-affinity antagonists were instrumental in revealing both pre- and postsynaptic functions of GBRs, establishing their critical role in maintaining the excitation-inhibition balance in the brain and highlighting their potential as therapeutic targets. The molecular cloning of GBR subunits enabled the generation of GBR knock-out mouse models, allowing assignment of distinct functions to pharmacologically indistinguishable receptor subtypes and the establishment of causal links between receptor dysfunction and pathological conditions. Advances in high-throughput genomic technologies, particularly whole-exome sequencing, have uncovered hundreds of variants in the genes encoding the GBR subunits, GABBR1 and GABBR2 , many of which are linked to neurological and psychiatric disorders. Functional characterization of such variants in recombinant assay systems has revealed both gain-of-function (GOF) and loss-of-function (LOF) mutations, which can now be interpreted in the context of high-resolution structural models of GBR activation. Moreover, proteomic studies have revealed that GBRs form macromolecular complexes with a diverse array of auxiliary proteins that modulate their trafficking, localization, signaling kinetics, and ion channel coupling. Variants in several of these GBR-associated proteins have now also been linked to human disease, with some shown to selectively impair presynaptic GBR functions in relevant mouse models. Here, we review the genetic evidence linking GBR dysfunction to human disease and emphasize the critical role of functional analyses of genetic variants in enhancing diagnostic precision and guiding therapeutic strategies.

GABA B receptors (GABA B Rs) are G protein-coupled receptors for γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Pathogenic variants in the GABBR1 and GABBR2 genes, which encode the GB1 and GB2 subunits of GABA B Rs, are implicated in several neurological and developmental disorders, including epilepsy and autism. Here we present a 7-year-old boy with Level 3 Autism Spectrum Disorder who carries a de novo heterozygous missense GABBR2 p.Arg212Gln variant. This variant was identified through whole exome sequencing and classified as variant of unknown significance (VUS). Treatment with the GABA B R agonist baclofen showed no clinical improvement, raising the question whether this VUS is responsible for the patient’s phenotype. We conducted a study to investigate the impact of the GABBR2 p.Arg212Gln and the previously reported GABBR2 p.Arg212Trp variants on protein structure and receptor activity. This study utilized a combination of molecular dynamics (MD) simulations, and in vitro experiments. Our simulations demonstrate that both amino acid substitutions locally alter amino acid interactions in the extracellular domain of GB2. Most importantly, the substitutions influence the positioning of transmembrane helices, shifting the conformation towards an active state with GABBR2 p.Arg212Gln and an inactive state with GABBR2 p.Arg212Trp. Functional assays confirmed the MD predictions, as evidenced by increased constitutive activity and enhanced potency of GABA for GABBR2 p.Arg212Gln, and a decreased constitutive activity with a loss of GABA potency for GABBR2 p.Arg212Trp. Our findings demonstrate the utility of MD simulations in predicting the functional consequences of VUS. Clarifying the pathogenic mechanisms associated with gene variants will aid in the identification of personalized treatment approaches.

GABA B receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer’s disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer’s disease increases Aβ formation. The mechanisms that control the presynaptic abundance of GABAB receptors (GBRs) remains unclear. This study shows that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs, and that selective loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression

GABA receptors (GBRs) are G protein-coupled receptors that mediate the actions of the inhibitory neurotransmitter GABA in the central nervous system. Early pharmacological studies with the GBR agonist baclofen and high-affinity antagonists were instrumental in revealing both pre- and postsynaptic functions of GBRs, establishing their critical role in maintaining the excitation-inhibition balance in the brain and highlighting their potential as therapeutic targets. The molecular cloning of GBR subunits enabled the generation of GBR knock-out mouse models, allowing assignment of distinct functions to pharmacologically indistinguishable receptor subtypes and the establishment of causal links between receptor dysfunction and pathological conditions. Advances in high-throughput genomic technologies, particularly whole-exome sequencing, have uncovered hundreds of variants in the genes encoding the GBR subunits, and , many of which are linked to neurological and psychiatric disorders. Functional characterization of such variants in recombinant assay systems has revealed both gain-of-function (GOF) and loss-of-function (LOF) mutations, which can now be interpreted in the context of high-resolution structural models of GBR activation. Moreover, proteomic studies have revealed that GBRs form macromolecular complexes with a diverse array of auxiliary proteins that modulate their trafficking, localization, signaling kinetics, and ion channel coupling. Variants in several of these GBR-associated proteins have now also been linked to human disease, with some shown to selectively impair presynaptic GBR functions in relevant mouse models. Here, we review the genetic evidence linking GBR dysfunction to human disease and emphasize the critical role of functional analyses of genetic variants in enhancing diagnostic precision and guiding therapeutic strategies.

GABA receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Aβ formation.

Dendritic spines are the locus for excitatory synaptic transmission in the brain and thus play a major role in neuronal plasticity. The ability to alter synaptic connections includes volumetric changes in dendritic spines that are driven by scaffolds created by the extracellular matrix (ECM). Here, we review the effects of the proteolytic activity of ECM proteases in physiological and pathological structural plasticity. We use matrix metalloproteinase-9 (MMP-9) as an example of an ECM modifier that has recently emerged as a key molecule in regulating the morphology and dysmorphology of dendritic spines that underlie synaptic plasticity and neurological disorders, respectively. We summarize the influence of MMP-9 on the dynamic remodeling of the ECM via the cleavage of extracellular substrates. We discuss its role in the formation, modification, and maintenance of dendritic spines in learning and memory. Finally, we review research that implicates MMP-9 in aberrant synaptic plasticity and spine dysmorphology in neurological disorders, with a focus on morphological abnormalities of dendritic protrusions that are associated with epilepsy.

At chemical synapses, synaptic vesicles release their acidic contents into the cleft leading to the expectation that the cleft should acidify. However, fluorescent pH probes targeted to the cleft of conventional glutamatergic synapses in both fruit flies and mice reveal cleft alkalinization, rather than acidification. Here, using a reaction-diffusion scheme, we modeled pH dynamics at the Drosophila neuromuscular junction (NMJ) as glutamate, adenosine triphosphate (ATP) and protons (H+) are released into the cleft. The model incorporates bicarbonate and phosphate buffering systems as well as plasma membrane calcium-ATPase (PMCA) activity and predicts substantial cleft acidification but only for fractions of a millisecond following neurotransmitter release. Thereafter, the cleft rapidly alkalinizes and remains alkaline for over 100 milliseconds, as the PMCA removes H+ from the cleft in exchange for calcium ions (Ca2+) from adjacent pre- and post-synaptic compartments; thus recapitulating the empirical data. The extent of synaptic vesicle loading and time course of exocytosis has little influence on the magnitude of acidification. Phosphate, but not bicarbonate buffering is effective at ameliorating the magnitude and time course of the acid spike, while both buffering systems are effective at ameliorating cleft alkalinization. The small volume of the cleft levies a powerful influence on the magnitude of alkalinization and its time course. Structural features that open the cleft to adjacent spaces appear to be essential for alleviating the extent of pH disturbances accompanying neurotransmission. Acid-base imbalances have surprisingly potent neurological effects highlighting the acute pH sensitivity of many neural mechanisms. Acid-Sensing Ion-Channels (ASICs), which open in response to acid shifts in extracellular pH, are an example of such a mechanism. However, while ASICs open during neurotransmission at conventional glutamatergic synapses, pH-sensitive electrodes and fluorophores show no signs of acidification at these synapses, only alkalinization. To resolve this paradox, we built a computational model which allows a glimpse beyond the experimental limitations of pH-sensitive electrodes and fluorophores. Our model reveals a highly dynamic pH landscape within the synaptic cleft, harboring deep but exceedingly rapid acid transients that give way to a prolonged period of alkalinization, thus reconciling ASIC activation with direct measurements of extracellular pH.

Glutamate receptor auxiliary proteins control receptor distribution and function, ultimately controlling synapse assembly, maturation and plasticity. At the Drosophila neuromuscular junction (NMJ), a synapse with both pre- and post-synaptic kainate-type glutamate receptors (KARs), we show that the auxiliary protein Neto evolved functionally distinct isoforms to modulate synapse development and homeostasis. Using genetics, cell biology and electrophysiology we demonstrate that Neto-α functions on both sides of the NMJ. In muscle, Neto-α limits the size of the postsynaptic receptors field. In motor neurons, Neto-α controls neurotransmitter release in a KAR-dependent manner. Furthermore, Neto-α is both required and sufficient for the presynaptic increase in neurotransmitter release in response to reduced postsynaptic sensitivity. This KAR-independent function of Neto-α is involved in activity-induced cytomatrix remodeling. We propose that Drosophila ensured NMJ functionality by acquiring two Neto isoforms with differential expression patterns and activities.