Formation of Presynaptic Terminals at Predefined Sites along Axons

Sabo, Shasta L.; Gomes, Raquel A.; McAllister, A. Kimberley

doi:10.1523/jneurosci.2052-06.2006

Cited by 111 publications

(176 citation statements)

References 70 publications

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“…Synaptic vesicles are a key component of presynaptic terminals, and GFP fusions of synaptic vesicle proteins such as Syn-GFP have been used widely to study the dynamics of presynaptic ter-minals. The stability of puncta containing presynaptic vesicle protein is a good indicator of functional presynaptic terminals (6,26,27). We therefore chose to image Syn-GFP dynamics in these experiments.…”

Section: Resultsmentioning

confidence: 99%

Regulation of synaptic stability by AMPA receptor reverse signaling

Ripley

Otto

Tiglio

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The establishment of neuronal circuits relies on the stabilization of functionally appropriate connections and the elimination of inappropriate ones. Here we report that postsynaptic AMPA receptors play a critical role in regulating the stability of glutamatergic synapses. Removal of surface AMPA receptors leads to a decrease in the number and stability of excitatory presynaptic inputs, whereas overexpression increases synapse number and stability. Furthermore, overexpression of AMPA receptors along with Neuroligin-1 in 293T cells is sufficient to stabilize presynaptic inputs from cortical neurons onto heterologous cells. The stabilization of presynaptic inputs by AMPA receptors is not dependent on receptor-mediated current and instead relies on structural interactions mediated by the N-terminal domain of the glutamate receptor 2 (GluR2) subunit. These observations indicate that transsynaptic signaling mediated by the extracellular domain of GluR2 regulates the stability of presynaptic terminals.GluR2 N-terminal domain | Presynaptic stabilization | Presynaptic input dynamics T he development of neural circuits is characterized by exuberant synapse formation followed by elimination of inappropriate connections (1-4). Although there is considerable evidence that activity-dependent mechanisms are involved in synapse elimination, the mechanisms responsible for regulating and maintaining stable synapses are largely unknown.Synapse formation is a dynamic process and involves the rapid recruitment of several synaptic proteins to sites of axo-dendritic contact. Transport packets containing essential components of the presynaptic active zone are highly motile before they reach synaptic sites (5). Likewise, synaptic vesicles traffic rapidly along axons before stabilizing at dendritic contact sites (6), suggesting that a dendrite-associated signal regulates presynaptic stability. At glutamatergic synapses, AMPA and NMDA receptors are recruited to the postsynaptic density in 1 h or less (7,8), raising the possibility that they may play an important role in regulating synapse stability.Electrophysiological and immunohistochemical experiments suggest that a large percentage of young synapses contain NMDA receptors but lack AMPA receptors (9, 10). AMPA receptors are recruited gradually to postsynaptic sites, resulting in an increase in the AMPA/NMDA ratio at these synapses (11-13). The increase in the AMPA/NMDA ratio correlates with the stabilization of dendritic spines.Synapse formation requires the precise apposition of presynaptic and postsynaptic elements underlying the need for bidirectional signaling. Key postsynaptic proteins such as neuroligins, synaptic cell-adhesion molecules (SynCAMs), Ephrin type B (EphB) receptors, netrin G ligands, and leucine-rich repeat transmembrane (LRRTM) proteins signal transsynaptically to induce recruitment of presynaptic components (14)(15)(16)(17)(18)(19)(20). Postsynaptic adhesion molecules also are involved in the functional maturation of presynaptic inputs (21-23). Recent work demons...

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Section: Resultsmentioning

confidence: 99%

Regulation of synaptic stability by AMPA receptor reverse signaling

Ripley

Otto

Tiglio

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…49,50 Cycling of synaptic vesicle protein transport vesicles at predefined sites along the axon appears to selectively attract dendritic filopodia and initiate synapse formation. 51 Furthermore, although vesicular glutamate Note that wt-GFP neurons surrounded by Het neurons undergo LTP, whereas Het neurons surrounded by wt-GFP neurons fail to potentiate (frequency (Hz) pre-gly: control = 0.99 ± 0.09 (n = 16), wt-GFP/Het = 0.96 ± 0.2 (n = 5), Het/wt-GFP = 1.06 ± 0.11 (n = 8); 20 ± 5 min: control = 1.30 ± 0.1 (n = 15), wt-GFP/Het = 1.19 ± 0.07 (n = 3), Het/wt-GFP = 0.88 ± 0.13 (n = 8); 60 ± 5 min: control = 1.27 ± 0.1 (n = 7), wt-GFP/Het = 1.18 ± 0.10 (n = 2), Het/wt-GFP = 0.83 ± 0.13 (n = 5); n is the number of cells; ctr versus ctr 20 min: P = 0.04, Mann-Withney rank-sum test. Amplitude (pA) pre-gly: control = 0.99 ± 0.04, wt-GFP/Het = 0.99 ± 0.07, Het/wt-GFP = 0.97 ± 0.09; 20 ± 5 min: control = 1.17 ± 0.06, wt-GFP/Het = 1.13 ± 0.10, Het/wt-GFP = 0.88 ± 0.12; 60 ± 5 min: control = 1.34 ± 0.08,wt-GFP/Het = 1.23 ± 0.07, Het/wt-GFP = 0.84 ± 0.09; ctr versus ctr 20 min: P = 0.03, ctr versus ctr 60 min: P = 0.2; Mann-Withney rank-sum test; 3 independent experiments).…”

Section: Discussionmentioning

confidence: 99%

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

et al. 2015

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Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels -as occurring in schizophrenia -may contribute to the pathology through an effect on postsynaptic function and plasticity. Cell Death and Differentiation (2015) 22, 1425-1436 doi:10.1038/cdd.2014 published online 13 February 2015 Synapses are complex cellular junctions specialized for communication between neurons. Epidemiological and genetic studies demonstrated that deficiencies in synapse function 1 are implicated in a wide range of brain disorders, including neurodegenerative 2 and psychiatric diseases such as schizophrenia 3,4 and autism. 5,6 A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. Therefore, the loss or modification of key synaptic proteins might directly affect the properties of such networks and, ultimately, synaptic function.SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis 7,8 and which has a role in the regulation of voltage-gated calcium channels. 9,10 The SNAP25 gene has been associated with attention deficit hyperactivity disorder (ADHD) 11,12 and with schizophrenia. 13,14 Consistently, SNAP-25 levels are lower in the hippocampus 15 and in the frontal lobe 16 of patients with schizophrenia. DNA variants of the SNAP25 gene that associate with ADHD are also associated with reduced expression level of the transcript in prefrontal cortex. 17 Finally, reduction of SNAP-25 levels has been found to cause neurodegeneration in mice lacking the synaptic vesicle protein Cysteine-string protein-α, possibly due to the impaired SNARE-complex assembly produced by the decreased SNAP-25. 18 The mechanisms by which reduced SNAP-25 expression may result in a psychiatric disease are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. 19,20 Recently an unexpected postsynaptic role of SNAP-25 has been described, with the protein controlling NMDA and kainate receptor trafficking. 21 Furthermore, it has been lately ...

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“…Here, chronic inactivation of axonal α7 nAChRs increased the number and size of glutamatergic presynaptic boutons, particularly those with the appearance of en passant boutons along glutamatergic axons. Studies in Caenorhabditis elegans and in rodent cortical cultures suggest that initial formation of presynaptic terminals can occur preferentially at predefined sites within axons in the absence of postsynaptic targets such as neuronal or glial contacts, suggesting that many en passant synapses form specifically and autonomously at predefined sites in developing axons (30)(31)(32). As α7 nAChRs are present within these enlarged boutons, and as en passant boutons are increased and enlarged upon inactivation of α7 nAChR, axonal α7 nAChRs may be an intrinsic factor within glutamatergic axons that modulates the formation of presynaptic boutons.…”

Section: Discussionmentioning

confidence: 99%

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

Lin

Vicini

Hsu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In association with NMDA receptors (NMDARs), neuronal α7 nicotinic ACh receptors (nAChRs) have been implicated in neuronal plasticity as well as neurodevelopmental, neurological, and psychiatric disorders. However, the role of presynaptic NMDARs and their interaction with α7 nAChRs in these physiological and pathophysiological events remains unknown. Here we report that axonal α7 nAChRs modulate presynaptic NMDAR expression and structural plasticity of glutamatergic presynaptic boutons during early synaptic development. Chronic inactivation of α7 nAChRs markedly increased cell surface NMDAR expression as well as the number and size of glutamatergic axonal varicosities in cortical cultures. These boutons contained presynaptic NMDARs and α7 nAChRs, and recordings from outside-out pulled patches of enlarged presynaptic boutons identified functional NMDAR-mediated currents. Multiphoton imaging of presynaptic NMDAR-mediated calcium transients demonstrated significantly larger responses in these enlarged boutons, suggesting enhanced presynaptic NMDAR function that could lead to increased glutamate release. Moreover, whole-cell patch clamp showed a significant increase in synaptic charge mediated by NMDAR miniature EPSCs but no alteration in the frequency of AMPAR miniature EPSCs, suggesting the selective enhancement of postsynaptically silent synapses upon inactivation of α7 nAChRs. Taken together, these findings indicate that axonal α7 nAChRs modulate presynaptic NMDAR expression and presynaptic and postsynaptic maturation of glutamatergic synapses, and implicate presynaptic α7 nAChR/NMDAR interactions in synaptic development and plasticity. silent synapse | synaptic development | synaptic plasticity | alpha bungarotoxin | cytisine

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Formation of Presynaptic Terminals at Predefined Sites along Axons

Cited by 111 publications

References 70 publications

Regulation of synaptic stability by AMPA receptor reverse signaling

Regulation of synaptic stability by AMPA receptor reverse signaling

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

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