Silencing synapses

Caleo, Matteo; Restani, Laura; Perry, V. Hugh

doi:10.4161/pri.23327

Cited by 5 publications

(6 citation statements)

References 31 publications

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“…Also, in amyotrophic lateral sclerosis, synapses at the neuromuscular junction degenerate prior to the cell body. It is suggested that the presynaptic degeneration occurs independent of synaptic activity and synaptic vesicle recycling (38, 39), and that the synaptic loss is a neuron-autonomous event facilitated without direct involvement of microglial cells (40). Understanding mechanisms of synapse degeneration will be crucial, as cognitive decline is strongly correlated with loss of presynaptic terminals.…”

Section: Microglial Functions In the Cnsmentioning

confidence: 99%

Ontogeny and Functions of Central Nervous System Macrophages

Katsumoto

Miranda

et al. 2014

The Journal of Immunology

126

104

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Microglia, the only non-neuroepithelial cells found in the parenchyma of the central nervous system (CNS), originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5-10 in mice). Thereafter, microglia are maintained independently of any input from the blood and in particular do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis and synaptic interactions. Here we discuss physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology.

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Section: Microglial Functions In the Cnsmentioning

confidence: 99%

Ontogeny and Functions of Central Nervous System Macrophages

Katsumoto

Miranda

et al. 2014

The Journal of Immunology

126

104

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“…BoNTs have been extensively used in both in vitro and in vivo experiments to study synaptic functionality (Caleo & Restani, 2018; Caleo et al, 2013). They target specific components of the SNARE complex, thus impairing synaptic membrane fusion and, as a consequence, neurotransmitter release.…”

Section: Discussionmentioning

confidence: 99%

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

Panzi

Lazo²,

Surana

et al. 2023

Preprint

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Pathological tau aggregates propagate across functionally connected neuronal networks in human neurodegenerative pathologies, such as Alzheimer's disease. However, the mechanism underlying this process is poorly understood. Several studies have showed that tau release is dependent on neuronal activity and that pathological tau is found in the extracellular space in free form, as well as in the lumen of extracellular vesicles. We recently showed that metabotropic glutamate receptor activity and the SNAP25 integrity modulate the release of pathological tau from human and mouse synaptosomes. Here, we have leveraged botulinum neurotoxins (BoNTs), which impair neurotransmitter release by cleaving specific synaptic SNARE proteins, to dissect molecular mechanisms related to tau release at synapses. In particular, we have tested the effect of botulinum neurotoxin A (BoNT/A) on the synaptic release of tau in primary mouse neurons. Hippocampal neurons were grown in microfluidic chambers and transduced with lentiviruses expressing human tau (hTau). We found that neuronal stimulation significantly increases the release of mutant hTau, whereas wild-type hTau is unaffected. Importantly, BoNT/A blocks mutant hTau release, indicating that this process is modulated by SNAP25 in intact neurons. These results suggest that BoNTs are potent tools to study the spreading of pathological proteins in neurodegenerative diseases and will play a central role in identifying novel molecular targets for the development of therapeutic interventions to treat tauopathies.

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“…At the ultrastructural level, our group investigated the morphological changes induced by local delivery of BoNT/A into the hippocampus [ 30 , 31 ]. Hippocampal samples were analyzed at different times following BoNT/A injection (2, 4, 8 weeks).…”

Section: Action Of Bonts On Central Synaptic Terminalsmentioning

confidence: 99%

“…The morphology of the degenerating synapses was also indistinguishable between the two groups. These experiments challenge the idea that dysfunctions in synaptic vesicle release trigger the elimination of synaptic boutons, at least in prion-induced neurodegeneration [ 30 , 31 ].…”

Section: Exploiting Bonts In Pathological Brain Conditionsmentioning

confidence: 99%

Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology

Caleo

Restani

2018

Toxins

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Botulinum neurotoxins are metalloproteases that specifically cleave N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed us to investigate specifically the role of synaptic activity in different physiological and pathological processes. The silencing properties of BoNTs can be exploited for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways.

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Silencing synapses

Cited by 5 publications

References 31 publications

Ontogeny and Functions of Central Nervous System Macrophages

Ontogeny and Functions of Central Nervous System Macrophages

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology

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