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Synaptic Vesicle Proteins and Active Zone Plasticity.

Kittel RJ, Heckmann M - Front Synaptic Neurosci (2016)

Bottom Line: The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission.Importantly, structural and functional properties of AZs vary significantly, even for a given connection.Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Institute of Physiology, Julius-Maximilians-University Würzburg Würzburg, Germany.

ABSTRACT
Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

No MeSH data available.


Related in: MedlinePlus

Synaptotagmin-1 (Syt1) and Rab3 shape active zone (AZ) differentiation and ultrastructure. (A) Illustration of the molecular complexity of the AZ. Syt1 (blue) and Rab3 (green) are highlighted. The numbers indicate core AZ proteins mentioned in the text: (1) VGCC; (2) Bassoon; (3) CAST; (4) Munc-13/18; (5) RIM; (6) Liprin-α. Modified from Goodsell (2009; © by The International Union of Biochemistry and Molecular Biology). (B) Shown are confocal images of the terminal three boutons along a type Ib axon branch. Staining against the membrane marker HRP (magenta) and Brp (green) illustrates the reduced number of AZs in rab3 mutant (rab3rup) and sytKD motoneurons. Note the small boutons at the sytKD neuromuscular junction (NMJ). Taken from Paul et al. (2015). (C) Super-resolution imaging of Brp by dSTORM (direct stochastic optical reconstruction microscopy; Heilemann et al., 2008). Examples of Brp organization at control and sytKD AZs (Paul et al., 2015) and the massively enlarged cytomatrix at the active zone (CAZ) frequently observed at rab3rup NMJs (Graf et al., 2009; Ehmann et al., 2014). (D) Quantification of the AZ gradient along type Ib motoneurons (left, related to B) and the nanoscopic organization of Brp at the CAZ (right, related to C). Summary of data presented in Ehmann et al. (2014) and Paul et al. (2015).
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Figure 1: Synaptotagmin-1 (Syt1) and Rab3 shape active zone (AZ) differentiation and ultrastructure. (A) Illustration of the molecular complexity of the AZ. Syt1 (blue) and Rab3 (green) are highlighted. The numbers indicate core AZ proteins mentioned in the text: (1) VGCC; (2) Bassoon; (3) CAST; (4) Munc-13/18; (5) RIM; (6) Liprin-α. Modified from Goodsell (2009; © by The International Union of Biochemistry and Molecular Biology). (B) Shown are confocal images of the terminal three boutons along a type Ib axon branch. Staining against the membrane marker HRP (magenta) and Brp (green) illustrates the reduced number of AZs in rab3 mutant (rab3rup) and sytKD motoneurons. Note the small boutons at the sytKD neuromuscular junction (NMJ). Taken from Paul et al. (2015). (C) Super-resolution imaging of Brp by dSTORM (direct stochastic optical reconstruction microscopy; Heilemann et al., 2008). Examples of Brp organization at control and sytKD AZs (Paul et al., 2015) and the massively enlarged cytomatrix at the active zone (CAZ) frequently observed at rab3rup NMJs (Graf et al., 2009; Ehmann et al., 2014). (D) Quantification of the AZ gradient along type Ib motoneurons (left, related to B) and the nanoscopic organization of Brp at the CAZ (right, related to C). Summary of data presented in Ehmann et al. (2014) and Paul et al. (2015).

Mentions: Rab3 is a small synaptic vesicle-associated GTPase involved in vesicle cycling, docking and exocytosis (Figure 1A; Südhof, 2004). In a seminal study on Rab3 function in Drosophila, Graf et al. reported that Rab3 also controls the protein composition of AZs. At rab3 mutant NMJs the number of Brp positive AZs drops down to about 30%. At the same time, individual AZs containing Brp are dramatically enlarged, these sites frequently display multiple T-bars and accumulate VGCCs (Figures 1B–D; Graf et al., 2009). According to quantitative super-resolution imaging, the number of Brp molecules at the fraction of available sites is increased on average 1.6-fold and correspondingly release probability at these AZs increases with increasing Brp content (Peled and Isacoff, 2011; Ehmann et al., 2014). Interestingly, late expression of rab3 can rescue the already manifested mutant phenotype, illustrating the dynamic control of Rab3 on the distribution and nucleation of Brp at AZs (Graf et al., 2009).


Synaptic Vesicle Proteins and Active Zone Plasticity.

Kittel RJ, Heckmann M - Front Synaptic Neurosci (2016)

Synaptotagmin-1 (Syt1) and Rab3 shape active zone (AZ) differentiation and ultrastructure. (A) Illustration of the molecular complexity of the AZ. Syt1 (blue) and Rab3 (green) are highlighted. The numbers indicate core AZ proteins mentioned in the text: (1) VGCC; (2) Bassoon; (3) CAST; (4) Munc-13/18; (5) RIM; (6) Liprin-α. Modified from Goodsell (2009; © by The International Union of Biochemistry and Molecular Biology). (B) Shown are confocal images of the terminal three boutons along a type Ib axon branch. Staining against the membrane marker HRP (magenta) and Brp (green) illustrates the reduced number of AZs in rab3 mutant (rab3rup) and sytKD motoneurons. Note the small boutons at the sytKD neuromuscular junction (NMJ). Taken from Paul et al. (2015). (C) Super-resolution imaging of Brp by dSTORM (direct stochastic optical reconstruction microscopy; Heilemann et al., 2008). Examples of Brp organization at control and sytKD AZs (Paul et al., 2015) and the massively enlarged cytomatrix at the active zone (CAZ) frequently observed at rab3rup NMJs (Graf et al., 2009; Ehmann et al., 2014). (D) Quantification of the AZ gradient along type Ib motoneurons (left, related to B) and the nanoscopic organization of Brp at the CAZ (right, related to C). Summary of data presented in Ehmann et al. (2014) and Paul et al. (2015).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4834300&req=5

Figure 1: Synaptotagmin-1 (Syt1) and Rab3 shape active zone (AZ) differentiation and ultrastructure. (A) Illustration of the molecular complexity of the AZ. Syt1 (blue) and Rab3 (green) are highlighted. The numbers indicate core AZ proteins mentioned in the text: (1) VGCC; (2) Bassoon; (3) CAST; (4) Munc-13/18; (5) RIM; (6) Liprin-α. Modified from Goodsell (2009; © by The International Union of Biochemistry and Molecular Biology). (B) Shown are confocal images of the terminal three boutons along a type Ib axon branch. Staining against the membrane marker HRP (magenta) and Brp (green) illustrates the reduced number of AZs in rab3 mutant (rab3rup) and sytKD motoneurons. Note the small boutons at the sytKD neuromuscular junction (NMJ). Taken from Paul et al. (2015). (C) Super-resolution imaging of Brp by dSTORM (direct stochastic optical reconstruction microscopy; Heilemann et al., 2008). Examples of Brp organization at control and sytKD AZs (Paul et al., 2015) and the massively enlarged cytomatrix at the active zone (CAZ) frequently observed at rab3rup NMJs (Graf et al., 2009; Ehmann et al., 2014). (D) Quantification of the AZ gradient along type Ib motoneurons (left, related to B) and the nanoscopic organization of Brp at the CAZ (right, related to C). Summary of data presented in Ehmann et al. (2014) and Paul et al. (2015).
Mentions: Rab3 is a small synaptic vesicle-associated GTPase involved in vesicle cycling, docking and exocytosis (Figure 1A; Südhof, 2004). In a seminal study on Rab3 function in Drosophila, Graf et al. reported that Rab3 also controls the protein composition of AZs. At rab3 mutant NMJs the number of Brp positive AZs drops down to about 30%. At the same time, individual AZs containing Brp are dramatically enlarged, these sites frequently display multiple T-bars and accumulate VGCCs (Figures 1B–D; Graf et al., 2009). According to quantitative super-resolution imaging, the number of Brp molecules at the fraction of available sites is increased on average 1.6-fold and correspondingly release probability at these AZs increases with increasing Brp content (Peled and Isacoff, 2011; Ehmann et al., 2014). Interestingly, late expression of rab3 can rescue the already manifested mutant phenotype, illustrating the dynamic control of Rab3 on the distribution and nucleation of Brp at AZs (Graf et al., 2009).

Bottom Line: The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission.Importantly, structural and functional properties of AZs vary significantly, even for a given connection.Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Institute of Physiology, Julius-Maximilians-University Würzburg Würzburg, Germany.

ABSTRACT
Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

No MeSH data available.


Related in: MedlinePlus