Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle

Bonnycastle, Katherine; Davenport, Elizabeth C.; Cousin, Michael A.

doi:10.1111/jnc.15035

Cited by 63 publications

(53 citation statements)

References 454 publications

(643 reference statements)

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“…Deficits in the transmission or processing of information are a common occurrence in neural disease. The role of synaptic plasticity and fatigue in pathology is thought to be a prominent one in neuropsychological disease and the loss of synaptic transmission may be a contributing factor to neurodegeneration (Crabtree and Gogos, 2014;Bonnycastle et al, 2020). The ability to assess the flow of information through a neural circuit can be crucial for understanding neural dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Upon fusion of synaptic vesicles at synapses, retrieval and internalization of plasma membrane requires clathrin-mediated or bulk endocytosis (Milosevic, 2018;Chanaday et al, 2019;Bonnycastle et al, 2020). After bulk endocytosis occurs, the clathrin-associated machinery is also needed at a later step to recycle large endocytic compartments into small vesicles (Kononenko and Haucke, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Temporal Vestibular Deficits in synaptojanin 1 (synj1) Mutants

Gao

Nicolson

2021

Front. Mol. Neurosci.

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The lipid phosphatase synaptojanin 1 (synj1) is required for the disassembly of clathrin coats on endocytic compartments. In neurons such activity is necessary for the recycling of endocytosed membrane into synaptic vesicles. Mutations in zebrafish synj1 have been shown to disrupt the activity of ribbon synapses in sensory hair cells. After prolonged mechanical stimulation of hair cells, both phase locking of afferent nerve activity and the recovery of spontaneous release of synaptic vesicles are diminished in synj1 mutants. Presumably as a behavioral consequence of these synaptic deficits, synj1 mutants are unable to maintain an upright posture. To probe vestibular function with respect to postural control in synj1 mutants, we developed a method for assessing the vestibulospinal reflex (VSR) in larvae. We elicited the VSR by rotating the head and recorded tail movements. As expected, the VSR is completely absent in pcdh15a and lhfpl5a mutants that lack inner ear function. Conversely, lhfpl5b mutants, which have a selective loss of function of the lateral line organ, have normal VSRs, suggesting that the hair cells of this organ do not contribute to this reflex. In contrast to mechanotransduction mutants, the synj1 mutant produces normal tail movements during the initial cycles of rotation of the head. Both the amplitude and temporal aspects of the response are unchanged. However, after several rotations, the VSR in synj1 mutants was strongly diminished or absent. Mutant synj1 larvae are able to recover, but the time required for the reappearance of the VSR after prolonged stimulation is dramatically increased in synj1 mutants. Collectively, the data demonstrate a behavioral correlate of the synaptic defects caused by the loss of synj1 function. Our results suggest that defects in synaptic vesicle recycling give rise to fatigue of ribbons synapses and possibly other synapses of the VS circuit, leading to the loss of postural control.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Temporal Vestibular Deficits in synaptojanin 1 (synj1) Mutants

Gao

Nicolson

2021

Front. Mol. Neurosci.

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“…Although it remains to be determined whether light‐activation of synaptoPAC induces pre‐synaptic facilitation at these other synapses, the newly developed optogenetic tool certainly opens an exciting potential line of research in the area of brain circuit analysis by enabling a much awaited counterpart to manipulations based on suppression of synaptic transmission. SynaptoPAC may also be beneficial in the understanding of pre‐synaptic failure in neurological disorders (Barthet & Mulle, 2020; Bonnycastle et al., 2020). It is tempting to speculate that light activation of synaptoPAC could counteract synaptic dysfunction in animal models of neurodevelopmental and degenerative disorders which present pre‐synaptic deficits (Barthet & Mulle, 2020; Bonnycastle et al., 2020).…”

Section: Figurementioning

confidence: 99%

Lighting up pre‐synaptic potentiation

Kees

Marneffe

Mulle

2020

Journal of Neurochemistry

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This is an Editorial Highlight of a manuscript by Oldani et al. (2020) (Oldani et al. 2020) in the current issue of the Journal of Neurochemistry, in which the authors describe synaptoPAC, a new optogenetic tool. SynaptoPAC is targeted to pre‐synaptic compartments and can be used for light‐induced increase of the levels of cAMP. Pre‐synaptic plasticity, defined as activity‐dependent modulation of neurotransmitter release, occurs over a variety of time scales. At a subset of synapses in the brain, long‐term forms of pre‐synaptic facilitation depend on an increase in the levels of cAMP. Light‐induced modulation of cAMP at synapses expressing cAMP‐dependent facilitation, has the great potential to mimic pre‐synaptic plasticity at genetically targeted synapses. Therefore, synaptoPAC constitutes a powerful tool to study the role of pre‐synaptic potentiation in the activity of selected neuronal circuits in relation to behaving animals with a high temporal and spatial precision.

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“…AP-2 is required for the fast retrieval of the SV cargo from the plasma membrane, whereas AP-1/AP-3 mediate the slower generation of vesicles from the endosomes (Cousin, 2017;Kononenko and Haucke, 2015;Mori and Takamori, 2018). The SV cycle is, therefore, highly dependent on many endocytic proteins working in synchrony, the perturbation of which has been linked to the etiology of several neurodevelopmental and neurodegenerative diseases (Bonnycastle et al, 2020;Waites and Garner, 2011). However, despite its essential role in synaptic transmission, the molecular mechanisms underlying SV recycling remain enigmatic.…”

Section: Introductionmentioning

confidence: 99%