Neurexins Regulate Presynaptic GABAB-Receptors at Central Synapses

Nature Communications 12, 2380 (2021)

DOI: 10.1038/s41467-021-22753-5

GABA_B-receptors are abundantly expressed in the nervous system and serve as the primary inhibitory neurotransmitters in mammalian brains. They play roles in Ca2+ channel modulation and regulation of presynaptic and postsynaptic inhibition, which ultimately impacts synaptic functioning and plasticity. Improper functioning of GABAB-receptors has been linked to a variety of neurological and psychiatric disorders. Obtaining a complete understanding of the formation and regulation of GABA_B-receptors and the relationships it forms with other proteins, molecules, and Ca2+ channels, is essential to understanding synaptic functioning. Recent studies suggest that cell adhesion molecules, known as neurexins, play a role in synaptic organization however their impact on general assembly of active zone signaling complexes, including GABA_B-receptors, remains unclear.

In this paper from Luo et al. in Nature Communications, the authors investigated the organization of the general assembly of active zone signaling complexes and the possible role neurexins play in their assembly. Their results suggest that neurexins play a role in the regulation of presynaptic GABA_B-receptor signaling within a variety of central synapses. The study compared synapses of control mice to neurexin-deficient synapses across four central synapse types, including both excitatory and inhibitory synapses, and found variation in the results of activation of GABA_B-receptor in all synapse types when lacking neurexins. This suggests neurexins play a role in mediating signaling and functioning of presynaptic GABA_B-receptors. The Vutara 352 super-resolution microscope was used to visualize GABA_B-receptor organization in 20 micron tissue sections of control and neurexin-deficient mice. Visualization and analysis revealed reduction in abundance and localization of presynaptic GABA_B-receptors, indicating neurexins’ involvement in the distribution of GABA_B-receptors.

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_SUBJECT(S):

• The molecular mechanisms underlying the formation, regulation, and relationships of GABA_B-receptors/signaling complexes
  
• The role of neurexins at the presynaptic active zone
  

_{FEATURED BRUKER TECHNOLOGY:}

_{KEY FINDINGS:}

• Neurexins are required for presynaptic GABA_B-receptor signaling complexes' localization and function
  
• Deletion of neurexins at several model synapses significantly reduced the sensitivity of neurotransmitter release to GABA_B-receptor activation
  
• Deletion of neurexins led to a loss of GABA_B-receptors from the presynaptic active zone of the calyx synapse

_{KEY TERMS:}

Activity-Dependent Development, FRET, GABA_B-Receptor, Inhibitory Synapses, Live-Cell Imaging, Molecular Neuroscience, Neurexin, Synaptic Transmission, Synaptic Vesicle Dynamics