Molecular and functional architecture of striatal dopamine release sites

Banerjee, Aditi; Imig, Cordelia; Balakrishnan, Karthik; Kershberg, Lauren; Lipstein, Noa; Uronen, Riikka-Liisa; Wang, Jie‐Xin; Cai, Xin; Benseler, Fritz; Rhee, Jeong Seop; Cooper, Benjamin H.; Liu, Changliang; Wojcik, Sonja M.; Kaeser, Pascal S.

doi:10.1016/j.neuron.2021.10.028

Cited by 30 publications

(54 citation statements)

References 116 publications

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“…Third, synaptic morphogenesis and structure does not require vesicular neurotransmitter release at glutamatergic synapses, as BoNT-C NMJs appear indistinguishable from wild type. Although several studies have shown neurotransmitter release is not necessary for the initial establishment of synapses (Banerjee et al, 2022; Sando et al, 2017; Sigler et al, 2017; Varoqueaux et al, 2002), whether miniature transmission was necessary for clustering of glutamate receptors at the fly NMJ has provoked some controversy (Otsu and Murphy, 2003; Saitoe et al, 2002a, 2002b; Verstreken and Bellen, 2002). It will be of significant interest in future studies to now determine the full electrophysiological properties of tonic vs phasic neurons, including vesicle pools, short term plasticity, and release probability across various extracellular Ca 2+ conditions.…”

Section: Discussionmentioning

confidence: 99%

Botulinum neurotoxin accurately separates tonic vs phasic transmission and reveals heterosynaptic plasticity rules in Drosophila

Han

Chien

Goel

et al. 2022

Preprint

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In developing and mature nervous systems, diverse neuronal subtypes innervate common targets to establish and maintain functional neural circuits. A major challenge towards understanding the structural and functional architecture of neural circuits is to separate these inputs and determine their intrinsic and heterosynaptic relationships. The Drosophila larval neuromuscular junction is a powerful model system to study these questions, where two glutamatergic motor neurons, the strong phasic-like Is and weak tonic-like Ib, co-innervate individual muscle targets to coordinate locomotor behavior. However, complete neurotransmission from each input has never been electrophysiologically separated. We have developed a botulinum neurotoxin, BoNT-C, that eliminates both spontaneous and evoked neurotransmission without perturbing synaptic growth or structure, enabling the first approach that accurately isolates input-specific neurotransmission. Selective expression of BoNT-C in Is or Ib motor inputs disambiguates functional properties of each input. Importantly, the composite values of Is and Ib neurotransmission can be fully recapitulated by isolated physiology from each input. Finally, selective silencing by BoNT-C does not induce heterosynaptic structural or functional plasticity at the convergent input. Thus, BoNT-C establishes the first approach to cleanly separate neurotransmission between tonic vs phasic neurons and defines heterosynaptic plasticity rules in a powerful model glutamatergic circuit.

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Section: Discussionmentioning

confidence: 99%

Botulinum neurotoxin accurately separates tonic vs phasic transmission and reveals heterosynaptic plasticity rules in Drosophila

Han

Chien

Goel

et al. 2022

Preprint

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“…The very low levels of an alternative variant of Munc13-1 left in Munc13-1 cKO neurons, described in Fig. S2 of (Banerjee et al, 2022), is not detected in these short exposures.…”

Section: Methodsmentioning

confidence: 77%

“…We used mice with floxed alleles for Munc13-1 and constitutive knockout alleles for Munc13-2 and Munc13-3 (Fig. S1A) (Augustin et al, 2001; Banerjee et al, 2022; Varoqueaux et al, 2002). In cultured neurons of these mice, Cre-expression removes Munc13-1 (cKO M ) without the potential for compensation by Munc13-2 or −3 because these genes are knocked out constitutively, and control experiments were performed on the same cultures but with expressing a lentivirus with an inactive Cre (control M ).…”

Section: Resultsmentioning

confidence: 99%

“…This analysis established that for both excitatory and inhibitory synapses, knockout of Munc13 on top of RIM and ELKS led to a significantly stronger reduction in synaptic transmission. The small amount of remaining release might be due to the low amount of exon 21/22-deficient Munc13-1 that persists after conditional Munc13-1 knockout with this allele (Banerjee et al, 2022), to Munc13-1 that persists beyond 11 days of Cre expression, to Munc13-3 that was not deleted in the hextuple knockout mice, or to an alternative release pathway that does not depend on RIM, ELKS and Munc13. Altogether, however, the data establish that the remaining synaptic transmission after RIM and ELKS knockout depends on the presence of Munc13-1 and Munc13-2.…”

Section: Resultsmentioning

confidence: 99%

“…Exons 2 (E2) and 3 (E3) were flanked by loxP sites in the conditional ELKS1α knockout mice, and exon 3 (E3) was flanked by loxP sites in conditional ELKS2α knockout mice. Floxed Munc13-1 mice (Banerjee et al, 2022) were crossed to constitutive knockout mice for Munc13-2 (Unc13b tm1Rmnd , RRID_MGI:2449706, (Varoqueaux et al, 2002)) and Munc13-3 (Unc13c tm1Bros , RRID_MGI:2449467, (Augustin et al, 2001)) to produce Munc13 homozygote knockout mice. Exon 21 (E21) was flanked by loxP sites in the conditional Munc13-1 knockout mice.…”

Section: Methodsmentioning

confidence: 99%

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Munc13 supports vesicle fusogenicity after disrupting active zone scaffolds and synaptic vesicle docking

Tan

Nola

Qiao

et al. 2022

Preprint

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Active zones consist of protein scaffolds that are tightly attached to the presynaptic plasma membrane. They dock and prime synaptic vesicles, couple them to Ca2+ entry, and target neurotransmitter release to postsynaptic receptor domains. Simultaneous RIM+ELKS ablation disrupts these scaffolds, abolishes vesicle docking and removes active zone-targeted Munc13, but some vesicles remain releasable. This enduring vesicular fusogenicity may be Munc13-independent or be mediated by non-active zone-anchored Munc13. We tested its Munc13-dependence by ablating Munc13-1 and Munc13-2 on top of RIM+ELKS in cultured hippocampal neurons. The hextuple knockout synapses lacked docked vesicles, but other ultrastructural features were near-normal despite the strong genetic manipulation. Removing Munc13 in addition to RIM+ELKS further impaired action potential-evoked release by decreasing the remaining pool of releasable vesicles. We conclude that Munc13 can support some fusogenicity without RIM and ELKS, and that presynaptic recruitment of Munc13, even without active zone-anchoring, suffices to generate some fusion-competent vesicles.

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