scholarly journals Temporal Vestibular Deficits in synaptojanin 1 (synj1) Mutants

2021 ◽  
Vol 13 ◽  
Author(s):  
Yan Gao ◽  
Teresa Nicolson
Keyword(s):  
Postural Control ◽  
Hair Cells ◽  
Synaptic Vesicles ◽  
Phase Locking ◽  
Vestibular Function ◽  
Loss Of Function ◽  
Vesicle Recycling ◽  
Ribbon Synapses ◽  
Synaptojanin 1 ◽  
Time Required

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.

scholarly journals Mutations in Synaptojanin Disrupt Synaptic Vesicle Recycling

2000 ◽  
Vol 150 (3) ◽  
pp. 589-600 ◽  
Author(s):  
Todd W. Harris ◽  
Erika Hartwieg ◽  
H. Robert Horvitz ◽  
Erik M. Jorgensen
Keyword(s):  
Plasma Membrane ◽  
Caenorhabditis Elegans ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Vesicle Trafficking ◽  
Synaptic Vesicle Recycling ◽  
Vesicle Recycling ◽  
Synaptojanin 1

Synaptojanin is a polyphosphoinositide phosphatase that is found at synapses and binds to proteins implicated in endocytosis. For these reasons, it has been proposed that synaptojanin is involved in the recycling of synaptic vesicles. Here, we demonstrate that the unc-26 gene encodes the Caenorhabditis elegans ortholog of synaptojanin. unc-26 mutants exhibit defects in vesicle trafficking in several tissues, but most defects are found at synaptic termini. Specifically, we observed defects in the budding of synaptic vesicles from the plasma membrane, in the uncoating of vesicles after fission, in the recovery of vesicles from endosomes, and in the tethering of vesicles to the cytoskeleton. Thus, these results confirm studies of the mouse synaptojanin 1 mutants, which exhibit defects in the uncoating of synaptic vesicles (Cremona, O., G. Di Paolo, M.R. Wenk, A. Luthi, W.T. Kim, K. Takei, L. Daniell, Y. Nemoto, S.B. Shears, R.A. Flavell, D.A. McCormick, and P. De Camilli. 1999. Cell. 99:179–188), and further demonstrate that synaptojanin facilitates multiple steps of synaptic vesicle recycling.

scholarly journals Mapping developmental maturation of inner hair cell ribbon synapses in the apical mouse cochlea

2019 ◽  
Vol 116 (13) ◽  
pp. 6415-6424 ◽  
Author(s):  
Susann Michanski ◽  
Katharina Smaluch ◽  
Anna Maria Steyer ◽  
Rituparna Chakrabarti ◽  
Cristian Setz ◽  
...  
Keyword(s):  
Hair Cells ◽  
Synaptic Vesicles ◽  
Molecular Assembly ◽  
General Mechanism ◽  
Inner Hair Cell ◽  
Synaptic Ribbon ◽  
Transport Pathways ◽  
Ribbon Synapses ◽  
Functional Maturation ◽  
Developmental Maturation

Ribbon synapses of cochlear inner hair cells (IHCs) undergo molecular assembly and extensive functional and structural maturation before hearing onset. Here, we characterized the nanostructure of IHC synapses from late prenatal mouse embryo stages (embryonic days 14–18) into adulthood [postnatal day (P)48] using electron microscopy and tomography as well as optical nanoscopy of apical turn organs of Corti. We find that synaptic ribbon precursors arrive at presynaptic active zones (AZs) after afferent contacts have been established. These ribbon precursors contain the proteins RIBEYE and piccolino, tether synaptic vesicles and their delivery likely involves active, microtubule-based transport pathways. Synaptic contacts undergo a maturational transformation from multiple small to one single, large AZ. This maturation is characterized by the fusion of ribbon precursors with membrane-anchored ribbons that also appear to fuse with each other. Such fusion events are most frequently encountered around P12 and hence, coincide with hearing onset in mice. Thus, these events likely underlie the morphological and functional maturation of the AZ. Moreover, the postsynaptic densities appear to undergo a similar refinement alongside presynaptic maturation. Blockwise addition of ribbon material by fusion as found during AZ maturation might represent a general mechanism for modulating ribbon size.

scholarly journals Expression and Localization of Ryanodine Receptors in the Frog Semicircular Canal

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Paola Perin ◽  
Laura Botta ◽  
Simona Tritto ◽  
Umberto Laforenza
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Semicircular Canal ◽  
Ryanodine Receptors ◽  
Cell Types ◽  
Sensory Epithelium ◽  
Rt Pcr ◽  
Supporting Cells ◽  
Vesicle Recycling ◽  
Ribbon Synapses

Several experiments suggest an important role for store-released Ca2+in hair cell organs: drugs targeting IP3and ryanodine (RyRs) receptors affect release from hair cells, and stores are thought to be involved in vesicle recycling at ribbon synapses. In this work we investigated the semicircular canal distribution of RyRs by immunofluorescence, using slice preparations of the sensory epithelium (to distinguish cell types) and flat mounts of the simpler nonsensory regions. RyRs were present in hair cells, mostly in supranuclear spots, but not in supporting cells; as regards nonsensory regions, they were also localized in dark cells and cells from the ductus. No labeling was found in nerve terminals, although nerve branches could be observed in proximity to hair cell RyR spots. The differential expression of RyR isoforms was studied by RT-PCR and immunoblotting, showing the presence of RyRαin both ampulla and canal arm and RyRβin the ampulla only.

scholarly journals Calcium-induced calcium release supports recruitment of synaptic vesicles in auditory hair cells

2016 ◽  
Vol 115 (1) ◽  
pp. 226-239 ◽  
Author(s):  
Manuel Castellano-Muñoz ◽  
Michael E. Schnee ◽  
Anthony J. Ricci
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Synaptic Vesicles ◽  
Calcium Release ◽  
Resting Potential ◽  
Calcium Stores ◽  
Potential Contribution ◽  
Auditory Hair Cells ◽  
Ribbon Synapses ◽  
Calcium Induced Calcium Release

Hair cells from auditory and vestibular systems transmit continuous sound and balance information to the central nervous system through the release of synaptic vesicles at ribbon synapses. The high activity experienced by hair cells requires a unique mechanism to sustain recruitment and replenishment of synaptic vesicles for continuous release. Using pre- and postsynaptic electrophysiological recordings, we explored the potential contribution of calcium-induced calcium release (CICR) in modulating the recruitment of vesicles to auditory hair cell ribbon synapses. Pharmacological manipulation of CICR with agents targeting endoplasmic reticulum calcium stores reduced both spontaneous postsynaptic multiunit activity and the frequency of excitatory postsynaptic currents (EPSCs). Pharmacological treatments had no effect on hair cell resting potential or activation curves for calcium and potassium channels. However, these drugs exerted a reduction in vesicle release measured by dual-sine capacitance methods. In addition, calcium substitution by barium reduced release efficacy by delaying release onset and diminishing vesicle recruitment. Together these results demonstrate a role for calcium stores in hair cell ribbon synaptic transmission and suggest a novel contribution of CICR in hair cell vesicle recruitment. We hypothesize that calcium entry via calcium channels is tightly regulated to control timing of vesicle fusion at the synapse, whereas CICR is used to maintain a tonic calcium signal to modulate vesicle trafficking.

scholarly journals Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

2021 ◽  
Vol 22 (12) ◽  
pp. 6497
Author(s):  
Anna Ghilardi ◽  
Alberto Diana ◽  
Renato Bacchetta ◽  
Nadia Santo ◽  
Miriam Ascagni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Hair Cells ◽  
Muscle Fibers ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Inner Ear Development ◽  
Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

scholarly journals Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

2015 ◽  
Vol 112 (38) ◽  
pp. 11965-11970 ◽  
Author(s):  
Li Zhu ◽  
Minghao Zhong ◽  
Gregory A. Elder ◽  
Mary Sano ◽  
David M. Holtzman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Genetic Risk ◽  
Primary Neurons ◽  
Loss Of Function ◽  
Sporadic Alzheimer’S Disease ◽  
Postmortem Human Brain ◽  
Apoe4 Allele ◽  
Synaptojanin 1

The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

Postural Control and Vestibular Function in Patients Selected for Cochlear Implantation

1995 ◽  
Vol 115 (sup520) ◽  
pp. 277-278 ◽  
Author(s):  
Måns Magnusson ◽  
Hannes Petersen ◽  
Sten Harris ◽  
Rolf Johansson
Keyword(s):  
Postural Control ◽  
Cochlear Implantation ◽  
Vestibular Function

scholarly journals Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

2013 ◽  
Vol 19 (4) ◽  
pp. 585-594 ◽  
Author(s):  
Laura Beth J. McIntire ◽  
Kyu-In Lee ◽  
Belle Chang-Ileto ◽  
Gilbert Di Paolo ◽  
Tae-Wan Kim
Keyword(s):  
Amyloid Β ◽  
Receptor Trafficking ◽  
Water Soluble ◽  
Amyloid Β Peptide ◽  
Screening Assay ◽  
Vesicle Recycling ◽  
Lipid Phosphatase ◽  
Phosphoinositide Phosphatase ◽  
Synaptojanin 1 ◽  
Behavioral Impairments

Elevation of amyloid β-peptide (Aβ) is critically associated with Alzheimer disease (AD) pathogenesis. Aβ-induced synaptic abnormalities, including altered receptor trafficking and synapse loss, have been linked to cognitive deficits in AD. Recent work implicates a lipid critical for neuronal function, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], in Aβ-induced synaptic and behavioral impairments. Synaptojanin 1 (Synj1), a lipid phosphatase mediating the breakdown of PI(4,5)P2, has been shown to play a role in synaptic vesicle recycling and receptor trafficking in neurons. Heterozygous deletion of Synj1 protected neurons from Aβ-induced synaptic loss and restored learning and memory in a mouse model of AD. Thus, inhibition of Synj1 may ameliorate Aβ-associated impairments, suggesting Synj1 as a potential therapeutic target. To this end, we developed a screening assay for Synj1 based on detection of inorganic phosphate liberation from a water-soluble, short-chain PI(4,5)P2. The assay displayed saturable kinetics and detected Synj1’s substrate preference for PI(4,5)P2 over PI(3,4,5)P3. The assay will enable identification of novel Synj1 inhibitors that have potential utility as chemical probes to dissect the cellular role of Synj1 as well as potential to prevent or reverse AD-associated synaptic abnormalities.

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