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Determinants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging.

ABSTRACT: Neural circuit function depends on the pattern of synaptic connections between neurons and the strength of those connections. Synaptic strength is determined by both postsynaptic sensitivity to neurotransmitter and the presynaptic probability of action potential evoked transmitter release (P_r). Whereas morphology and neurotransmitter receptor number indicate postsynaptic sensitivity, presynaptic indicators and the mechanism that sets P_r remain to be defined. To address this, we developed QuaSOR, a super-resolution method for determining P_r from quantal synaptic transmission imaging at hundreds of glutamatergic synapses at a time. We mapped the P_r onto super-resolution 3D molecular reconstructions of the presynaptic active zones (AZs) of the same synapses at the Drosophila larval neuromuscular junction (NMJ). We find that P_r varies greatly between synapses made by a single axon, quantify the contribution of key AZ proteins to P_r diversity and find that one of these, Complexin, suppresses spontaneous and evoked transmission differentially, thereby generating a spatial and quantitative mismatch between release modes. Transmission is thus regulated by the balance and nanoscale distribution of release-enhancing and suppressing presynaptic proteins to generate high signal-to-noise evoked transmission.

SUBMITTER: Newman ZL

PROVIDER: S-EPMC8752601 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Determinants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging.

Newman Zachary L ZL Bakshinskaya Dariya D Schultz Ryan R Kenny Samuel J SJ Moon Seonah S Aghi Krisha K Stanley Cherise C Marnani Nadia N Li Rachel R Bleier Julia J Xu Ke K Isacoff Ehud Y EY

Nature communications 20220111 1

Neural circuit function depends on the pattern of synaptic connections between neurons and the strength of those connections. Synaptic strength is determined by both postsynaptic sensitivity to neurotransmitter and the presynaptic probability of action potential evoked transmitter release (P<sub>r</sub>). Whereas morphology and neurotransmitter receptor number indicate postsynaptic sensitivity, presynaptic indicators and the mechanism that sets P<sub>r</sub> remain to be defined. To address this ...[more]

PMID: 35017509

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Project description:Neuronal circuits are composed of synapses that are either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through interneuronal gap junction channels. While the molecular complexity that controls chemical synapse structure and function is well appreciated, the proteins of electrical synapses beyond the gap-junction-forming Connexins are not well defined. Yet, electrical synapses are expected to be molecularly complex beyond the gap junctions. Connexins are integral membrane proteins requiring vesicular transport and membrane insertion/retrieval to achieve function, homeostasis, and plasticity. Additionally, electron microscopy of neuronal gap junctions reveals neighboring electron dense regions termed the electrical synapse density (ESD). To reveal the molecular complexity of the electrical synapse proteome, we used proximity-dependent biotinylation (TurboID) linked to neural Connexins in zebrafish. Proteomic analysis of developing and mature nervous systems identifies hundreds of Connexin-associated proteins, with overlapping and distinct representation during development and adulthood. The identified protein classes span cell adhesion molecules, cytoplasmic scaffolds, vesicular trafficking, and proteins usually associated with the post synaptic density (PSD) of chemical synapses. Using circuits with stereotyped electrical and chemical synapses, we define molecular sub-synaptic compartments of ESD localizing proteins, we find molecular heterogeneity amongst electrical synapse populations, and we examine the synaptic intermingling of electrical and chemical synapse proteins. Taken together, these results reveal a new complexity of electrical synapse molecular diversity and highlight a novel overlap between chemical and electrical synapse proteomes. Moreover, human homologs of the electrical synapse proteins are associated with autism, epilepsy, and other neurological disorders, providing a novel framework towards understanding neuro-atypical states.

Dataset Information

Determinants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging.

Publications

Determinants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging.

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