Abstract
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.
Highlights
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)
To assess potential defects in vestibular input and motor output in synj1 mutants, we developed a method for quantifying the vestibulospinal reflex (VSR) in zebrafish larvae
Our results indicate that synj1 mutants have a normal VSR that quickly declines after repetitive stimulation
Summary
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). The clathrin-associated machinery is needed at a later step to recycle large endocytic compartments into small vesicles (Kononenko and Haucke, 2015). Once formed, clathrin coated vesicles are relieved of their surface coats via the actions of synaptojanin lipid phosphatases. These enzymes remove phosphate groups from phosphoinositide lipids such as PI(4,5)P2, which promotes the release of the clathrin protein complex (Mani et al, 2007). Uncoated vesicles can rejoin the pool of synaptic vesicles for another cycle of neurotransmitter release.
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