FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

Activity-dependent bulk endocytosis (ADBE) is the dominant mode of synaptic vesicle endocytosis during high-frequency stimulation, suggesting it should play key roles in neurotransmission during periods of intense neuronal activity. However, efforts in elucidating the physiological role of ADBE have been hampered by the lack of identified molecules which are unique to this endocytosis mode. To address this, we performed proteomic analysis on purified bulk endosomes, which are a key organelle in ADBE. Bulk endosomes were enriched via two independent approaches, a classical subcellular fractionation method and isolation via magnetic nanoparticles. There was a 77% overlap in proteins identified via the two protocols, and these molecules formed the ADBE core proteome. Bioinformatic analysis revealed a strong enrichment in cell adhesion and cytoskeletal and signaling molecules, in addition to expected synaptic and trafficking proteins. Network analysis identified Rab GTPases as a central hub within the ADBE proteome. Subsequent investigation of a subset of these Rabs revealed that Rab11 both facilitated ADBE and accelerated clathrin-mediated endocytosis. These findings suggest that the ADBE proteome will provide a rich resource for the future study of presynaptic function, and identify Rab11 as a regulator of presynaptic function.

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SorCS1-mediated Sorting of Neurexin in Dendrites Maintains Presynaptic Function

10.1101/552695 ◽

2019 ◽

Author(s):

Luís F. Ribeiro ◽

Ben Verpoort ◽

Julie Nys ◽

Kristel M. Vennekens ◽

Keimpe D. Wierda ◽

...

Keyword(s):

Protein Composition ◽

Effector Protein ◽

Synaptic Membrane ◽

Surface Distribution ◽

Recycling Endosomes ◽

Surface Polarization ◽

Presynaptic Function ◽

Early Endosomes ◽

Sorting Receptor ◽

Activity Dependent

AbstractThe pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The mechanisms that maintain the polarized distribution of synaptic membrane proteins are poorly understood. The sorting receptor SorCS1 is a critical trafficking regulator of neuronal receptors, including neurexin (Nrxn), a presynaptic adhesion molecule essential for synaptic transmission. We find that SorCS1 controls a balance between axonal and dendritic Nrxn1α surface levels. Newly synthesized Nrxn1α traffics to the somatodendritic surface, followed by endocytosis. SorCS1 interacts with the Rab11 effector protein Rab11FIP5/Rip11 to facilitate the transition of internalized Nrxn1α from early to recycling endosomes and bias Nrxn1α surface polarization toward the axon. In the absence of SorCS1, Nrxn1α accumulates in early endosomes and mis-polarizes to the dendritic surface, impairing presynaptic function. The axonal/dendritic balance of Nrxn1α surface distribution is activity-dependent, indicating that SorCS1-mediated sorting in somatodendritic endosomes dynamically controls Nrxn1α axonal surface polarization required for proper presynaptic function.

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The Role of GSK3 in Presynaptic Function

International Journal of Alzheimer s Disease ◽

10.4061/2011/263673 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Karen Janet Smillie ◽

Michael Alan Cousin

Keyword(s):

Synaptic Vesicles ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase 3 ◽

Nerve Terminals ◽

The Past ◽

Presynaptic Function ◽

Signalling Cascades ◽

Synaptic Failure ◽

Activity Dependent

The past ten years of research have identified a number of key roles for glycogen synthase kinase 3 (GSK3) at the synapse. In terms of presynaptic physiology, critical roles for GSK3 have been revealed in the growth and maturation of the nerve terminal and more recently a key role in the control of activity-dependent bulk endocytosis of synaptic vesicles. This paper will summarise the major roles assigned to GSK3 in both immature and mature nerve terminals, the substrates GSK3 phosphorylates to exert its action, and how GSK3 activity is regulated by different presynaptic signalling cascades. The number of essential roles for GSK3, coupled with the numerous signalling cascades all converging to regulate its activity, suggests that GSK3 is a key integrator of multiple inputs to modulate the strength of neurotransmission. Modulation of these pathways may point to potential mechanisms to overcome synaptic failure in neurodegenerative disorders such as Alzheimer's disease.

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Roles for α-Synuclein in Gene Expression

Genes ◽

10.3390/genes12081166 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1166

Author(s):

Mahalakshmi Somayaji ◽

Zina Lanseur ◽

Se Joon Choi ◽

David Sulzer ◽

Eugene V. Mosharov

Keyword(s):

Gene Expression ◽

Physiological Role ◽

Function Mechanism ◽

Normal Functions ◽

Presynaptic Function ◽

Dependent Signal ◽

Expression Pathways ◽

Cellular Compartments ◽

Activity Dependent ◽

Familial Parkinson’S Disease

α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson’s disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.

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Synaptotagmin 7 is targeted to the axonal plasma membrane through γ-secretase processing to promote synaptic vesicle docking in mouse hippocampal neurons

eLife ◽

10.7554/elife.67261 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jason D Vevea ◽

Grant F Kusick ◽

Kevin C Courtney ◽

Erin Chen ◽

Shigeki Watanabe ◽

...

Keyword(s):

Plasma Membrane ◽

Synaptic Vesicle ◽

Synaptic Vesicles ◽

Hippocampal Neurons ◽

Glutamate Release ◽

Vesicle Docking ◽

Presynaptic Function ◽

Asynchronous Release ◽

Vesicle Cycle ◽

Activity Dependent

Synaptotagmin 7 (SYT7) has emerged as a key regulator of presynaptic function, but its localization and precise role in the synaptic vesicle cycle remain the subject of debate. Here, we used iGluSnFR to optically interrogate glutamate release, at the single-bouton level, in SYT7KO-dissociated mouse hippocampal neurons. We analyzed asynchronous release, paired-pulse facilitation, and synaptic vesicle replenishment and found that SYT7 contributes to each of these processes to different degrees. ‘Zap-and-freeze’ electron microscopy revealed that a loss of SYT7 diminishes docking of synaptic vesicles after a stimulus and inhibits the recovery of depleted synaptic vesicles after a stimulus train. SYT7 supports these functions from the axonal plasma membrane, where its localization and stability require both γ-secretase-mediated cleavage and palmitoylation. In summary, SYT7 is a peripheral membrane protein that controls multiple modes of synaptic vesicle (SV) exocytosis and plasticity, in part, through enhancing activity-dependent docking of SVs.

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Malfunctional Reorganization in the Developing Limbo-Prefrontal System in Animals: Implications for Human Psychoses?

Zeitschrift für Neuropsychologie ◽

10.1024//1016-264x.12.1.8 ◽

2001 ◽

Vol 12 (1) ◽

pp. 8-14

Author(s):

Gertraud Teuchert-Noodt ◽

Ralf R. Dawirs

Keyword(s):

Prefrontal Cortex ◽

Mental Disorders ◽

Dentate Gyrus ◽

Cognitive Functions ◽

Experimental Approach ◽

Regulatory Mechanisms ◽

Hippocampal Dentate Gyrus ◽

Non Invasive ◽

Invasive Method ◽

Activity Dependent

Abstract: Neuroplasticity research in connection with mental disorders has recently bridged the gap between basic neurobiology and applied neuropsychology. A non-invasive method in the gerbil (Meriones unguiculus) - the restricted versus enriched breading and the systemically applied single methamphetamine dose - offers an experimental approach to investigate psychoses. Acts of intervening affirm an activity dependent malfunctional reorganization in the prefrontal cortex and in the hippocampal dentate gyrus and reveal the dopamine position as being critical for the disruption of interactions between the areas concerned. From the extent of plasticity effects the probability and risk of psycho-cognitive development may be derived. Advance may be expected from insights into regulatory mechanisms of neurogenesis in the hippocampal dentate gyrus which is obviously to meet the necessary requirements to promote psycho-cognitive functions/malfunctions via the limbo-prefrontal circuit.

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