Presynaptic development is controlled by the core active zone proteins CAST/ELKS

Mapping Intimacies ◽

10.1101/823542 ◽

2019 ◽

Author(s):

Tamara Radulovic ◽

Wei Dong ◽

R. Oliver Goral ◽

Connon I. Thomas ◽

Priyadharishini Veeraraghavan ◽

...

Keyword(s):

Active Zone ◽

Morphological Properties ◽

Synapse Development ◽

Neuronal Circuit ◽

Early Stages ◽

Core Proteins ◽

Circuit Development ◽

Presynaptic Active Zone ◽

And Function ◽

Area And Volume

AbstractMany presynaptic active zone proteins have multiple regulatory roles that vary during distinct stages of neuronal circuit development. However, our understanding how presynaptic active zone proteins regulate synapse development during neuronal circuit maturation is in its early stages. Although CAST/ELKS are presynaptic active zone core proteins, their roles in synapse development in the mammalian central nervous system remain enigmatic. To unravel CAST/ELKS roles in glutamatergic synapse development, we analyzed how their loss during the early stages of circuit maturation impacted the calyx of Held presynaptic terminal development and function. We found a reduction in presynaptic surface area and volume, but an increase in active zone size. Additionally, we found a reduction in all presynaptic Cav2 channel subtype currents. Surprisingly, these changes did not impair synaptic transmission. We propose that CAST/ELKS are involved in pathways regulating presynaptic morphological properties and Cav2 channel subtype levels during early stages of neuronal circuit maturation.

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Loss of Piccolo function in rats induces Pontocerebellar Hypoplasia type 3-like phenotypes

10.1101/774422 ◽

2019 ◽

Author(s):

Joanne Falck ◽

Christine Bruns ◽

Sheila Hoffmann ◽

Isabelle Straub ◽

Erik J. Plautz ◽

...

Keyword(s):

Active Zone ◽

Motor Coordination ◽

Mossy Fiber ◽

Brain Size ◽

Pontocerebellar Hypoplasia ◽

Functional Link ◽

Genetic Studies ◽

Presynaptic Active Zone ◽

And Function ◽

Type 3

AbstractPiccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3), although a causal relationship is lacking. We have characterized recently generated knockout (Pclogt/gt) rats. Analysis revealed a dramatic reduction in brain size compared to wildtype (Pclowt/wt) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell (GC) layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber (MF) afferents from pontine neurons and the expression of the α6 GABAA receptor subunit at the MF-GC synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers (CFs). Ultrastructural and functional studies revealed a reduced size of MF boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together these data suggest that loss of Piccolo function in patients with PCH3 could be causal for many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder.Significance StatementPontocerebellar Hypoplasia type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the Piccolo gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo knockout rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with PCH3 are also exhibited by these Piccolo deficient animals.

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Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function

Molecular Neurobiology ◽

10.1007/s12035-015-9450-5 ◽

2015 ◽

Vol 53 (8) ◽

pp. 5203-5216

Author(s):

M. M. Hamza ◽

S. A. Rey ◽

P. Hilber ◽

A. Arabo ◽

T. Collin ◽

...

Keyword(s):

Neuronal Circuit ◽

Circuit Development ◽

And Function

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Amyloid Precursor Protein Knockout Diminishes Synaptic Vesicle Proteins at the Presynaptic Active Zone in Mouse Brain

Current Alzheimer Research ◽

10.2174/1567205011666141107152458 ◽

2014 ◽

Vol 11 (10) ◽

pp. 971-980 ◽

Cited By ~ 10

Author(s):

Melanie Laßek ◽

Jens Weingarten ◽

Amparo Acker-Palmer ◽

Sandra Bajjalieh ◽

Ulrike Muller ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Synaptic Vesicle ◽

Mouse Brain ◽

Active Zone ◽

Precursor Protein ◽

Presynaptic Active Zone ◽

Vesicle Proteins

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PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure

Nature Communications ◽

10.1038/s41467-021-23116-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Javier Emperador-Melero ◽

Man Yan Wong ◽

Shan Shan H. Wang ◽

Giovanni de Nola ◽

Hajnalka Nyitrai ◽

...

Keyword(s):

Phase Separation ◽

Active Zone ◽

Neurotransmitter Release ◽

Hippocampal Neurons ◽

Phosphorylation Site ◽

Double Knockout ◽

Zone Structure ◽

Presynaptic Nerve Terminal ◽

Condensate Formation ◽

And Function

AbstractThe active zone of a presynaptic nerve terminal defines sites for neurotransmitter release. Its protein machinery may be organized through liquid–liquid phase separation, a mechanism for the formation of membrane-less subcellular compartments. Here, we show that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation in transfected HEK293T cells. Condensate formation is triggered by Liprin-α3 PKC-phosphorylation at serine-760, and RIM and Munc13 are co-recruited into membrane-attached condensates. Phospho-specific antibodies establish phosphorylation of Liprin-α3 serine-760 in transfected cells and mouse brain tissue. In primary hippocampal neurons of newly generated Liprin-α2/α3 double knockout mice, synaptic levels of RIM and Munc13 are reduced and the pool of releasable vesicles is decreased. Re-expression of Liprin-α3 restored these presynaptic defects, while mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented this rescue. Finally, PKC activation in these neurons acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. Our findings indicate that PKC-mediated phosphorylation of Liprin-α3 triggers its phase separation and modulates active zone structure and function.

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From Progenitors to Progeny: Shaping Striatal Circuit Development and Function

Journal of Neuroscience ◽

10.1523/jneurosci.0620-21.2021 ◽

2021 ◽

Vol 41 (46) ◽

pp. 9483-9502

Author(s):

Rhys Knowles ◽

Nathalie Dehorter ◽

Tommas Ellender

Keyword(s):

Circuit Development ◽

And Function

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The Early Minoan Occupation of Knossos: A Note on some new Evidence.

Anatolian Studies ◽

10.2307/3642556 ◽

1972 ◽

Vol 22 ◽

pp. 115-128 ◽

Cited By ~ 3

Author(s):

John Evans

Keyword(s):

Bronze Age ◽

Early Years ◽

Major Obstacle ◽

Early Bronze Age ◽

Form And Function ◽

Long Period ◽

Early Stages ◽

And Function ◽

The Hill ◽

New Evidence

Following their discovery of the “Burnt Palace” at Beycesultan in the mid 1950's, Seton Lloyd and James Mellaart drew attention to a number of features of its architecture which seemed to indicate links with the palace architecture of Minoan Crete, and discussed the possible significance of these similarities (Lloyd and Mellaart, 1956 118–123, 1965 61, 62). Whatever this may be in terms of relationships between the two areas in the second millennium B.C., however, it seems clear that they cannot throw any light on the first appearance of palaces in Crete. The problems of the origin and development of the Cretan Bronze Age palaces are complex, and though they have been much discussed since the first excavations in the early years of the century, a major obstacle to progress has always been the lack of precise evidence, or even of any evidence at all, for the early stages of the process. As they stand, most of the palaces are the product of a series of rebuildings and remodellings over a long period, and it is not always clear just what they were like when first erected. Most frustrating of all, however, is the lack of evidence bearing on the question of whether they were preceded, during the Early Bronze Age, by buildings which were in any respect analogous in form and function. It has long been clear that the sites of some of the major Middle and Late Minoan palaces were occupied during the Early Minoan period, but at Phaistos and Knossos at any rate extensive clearing and levelling in preparation for the erection of the Middle Minoan palaces has obliterated practically all traces of the Early Minoan buildings. At Phaistos Branigan has hinted that the fragments of walls found by Pernier (1935, pl. VI) on the highest point of the hill might have belonged to a building of some consequence, possibly similar to the Early Minoan II mansion known as the House on the Hill at Vasiliki (Branigan 1970, p. 41). Branigan thinks that in addition to the rooms mentioned by Pernier, there may be traces of a corridor similar to that in the Vasiliki building. Only the bottom two courses of the walls survive, so that it is difficult to say much about their construction, though it seems to be poorer than that of the walls of some Early Minoan private houses later found by Levi on another part of the site.

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Synaptophysin 1 Clears Synaptobrevin 2 from the Presynaptic Active Zone to Prevent Short-Term Depression

Cell Reports ◽

10.1016/j.celrep.2016.01.031 ◽

2016 ◽

Vol 14 (6) ◽

pp. 1369-1381 ◽

Cited By ~ 26

Author(s):

Rajit Rajappa ◽

Anne Gauthier-Kemper ◽

Daniel Böning ◽

Jana Hüve ◽

Jürgen Klingauf

Keyword(s):

Active Zone ◽

Short Term ◽

Presynaptic Active Zone

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Phosphorylation triggers presynaptic phase separation of Liprin-α3 to control active zone structure

10.1101/2020.10.28.357574 ◽

2020 ◽

Author(s):

Javier Emperador-Melero ◽

Man Yan Wong ◽

Shan Shan H. Wang ◽

Giovanni de Nola ◽

Tom Kirchhausen ◽

...

Keyword(s):

Phase Separation ◽

Active Zone ◽

Neurotransmitter Release ◽

Phosphorylation Site ◽

Double Knockout ◽

Zone Structure ◽

And Function ◽

Pkc Activation ◽

Liquid Liquid Phase Separation

AbstractLiquid-liquid phase separation enables the assembly of membrane-less subcellular compartments, but testing its biological functions has been difficult. The presynaptic active zone, protein machinery in nerve terminals that defines sites for neurotransmitter release, may be organized through phase separation. Here, we discover that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation upon phosphorylation by PKC at a single site. RIM and Munc13 are co-recruited to membrane-attached condensates, and phospho-specific antibodies establish Liprin-α3 phosphorylation in vivo. At synapses of newly generated Liprin-α2/α3 double knockout mice, RIM, Munc13 and the pool of releasable vesicles were reduced. Re-expression of Liprin-α3 restored these defects, but mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented rescue. Finally, PKC activation acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. We conclude that Liprin-α3 phosphorylation rapidly triggers presynaptic phase separation to modulate active zone structure and function.

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