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bioRxiv · 10.64898/2025.12.10.693514

Presynaptic GABAB autoreceptors suppress neurotransmitter release during repetitive stimulation via the Gβγ-SNARE pathway.

Zurawski, Z.·Lu, I.·Alford, S.·Potcoava, M.·Delbove, C.·Peters, C. J.·hamm, h. e.
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Abstract

GABAergic signaling provides the brains primary inhibitory mechanism with defects linked to epilepsy, anxiety, depression, insomnia, schizophrenia and neurodegeneration. A key regulatory mechanism is autoinhibition of GABA release during repetitive activity via presynaptic Gi/o-coupled GABAB receptors, supporting synaptic tuning and memory formation, and limiting neurotransmitter spillover. Exogenous GABAB receptor agonists reduce presynaptic Ca2+ entry by inhibiting calcium channels. However, using transgenic mice expressing a mutant SNAP25 with diminished ability to bind G{beta}{gamma} (SNAP25{Delta}3), we show that suppression by GABAB autoreceptors requires intact G{beta}{gamma}-SNARE interactions. Imaging of presynaptic Ca2+ transients in GABAergic axons showed no GABA-mediated autoreceptor suppression of Ca2+ entry during stimulus trains. In contrast, application of the exogenous GABAB receptor agonist baclofen profoundly inhibited Ca2+ entry, which could be partially reversed by exogenously elevating cAMP, indicating a complementary role of inhibition of adenylyl cyclase. Baclofen reduced spontaneous IPSC frequency and amplitude and both effects were diminished in SNAP25{Delta}3 mice, consistent with inhibition at Ca2+ channels and SNARE complexes. Physiological GABA-mediated and exogenous GABAB receptor activation thus produce distinct outcomes on GABAergic neurotransmission, indicating that synthetic drug application to neurons does not faithfully recapitulate endogenous signaling pathways. We conclude that endogenous rapid GABAB autoreceptor signaling inhibits neurotransmitter release primarily by G{beta}{gamma}-mediated inhibitions of SNARE mechanisms, whereas prolonged agonist application additionally suppresses Ca2+ influx via cAMP signaling.

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Zurawski, Z., Lu, I., Alford, S., Potcoava, M., Delbove, C., Peters, C. J., hamm, h. e.. 2025-12-13. Presynaptic GABAB autoreceptors suppress neurotransmitter release during repetitive stimulation via the Gβγ-SNARE pathway.. https://doi.org/10.64898/2025.12.10.693514

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