BAI1 localises AMPA receptors at the cochlear afferent postsynaptic density and is
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ABSTRACT:
PROVIDER: PRJNA1069109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27731200_1.fastq.gz | Fastqsanger.gz | |||
| SRR27731200_2.fastq.gz | Fastqsanger.gz | |||
| SRR27731201_1.fastq.gz | Fastqsanger.gz | |||
| SRR27731201_2.fastq.gz | Fastqsanger.gz | |||
| SRR27731202_1.fastq.gz | Fastqsanger.gz |
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Project description:Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming axo-somatic synapses with inner hair cells (IHCs), the primary sensory receptors of the mammalian cochlea. Although IHC ribbon synapses have been extensively studied, the molecular mechanisms regulating the structure and function of the post-synaptic density (PSD) at the SGN afferent terminals are largely unknown. Using functional, morphological, and transcriptomic approaches, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1), encoded by the Adgrb1 gene, is required for the clustering of the glutamate AMPA receptors GluR2-4 to the SGN post-synaptic density. Adult mice expressing BAI1 lacking the N-terminal thrombospondin type 1 repeats (TRS) have functional IHC synapses but fail to transmit acoustic information to the SGNs, leading to highly raised auditory thresholds. We also found that in adult Bai1-deficient mice, despite the almost complete absence of AMPA receptors, the SGN fibres innervating the IHCs did not degenerate. RNA sequencing and western blotting also indicate that AMPA receptors are expressed in the cochlea of Bai1-deficient mice, highlights that BAI1 is involved is trafficking or anchoring GluR2-4 to the PSDs. Moreover, these results have identified novel molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.
2024-03-27 | GSE254269 | GEO
Project description:Scaffolding molecules at the postsynaptic membrane form the foundation of excitatory synaptic transmission by establishing the architecture of the postsynaptic density (PSD), but the small size of the synapse has precluded measurement of PSD organization in live cells. We measured the internal structure of the PSD in live neurons at approximately 25 nm resolution using photoactivated localization microscopy (PALM). We found that four major PSD scaffold proteins were each organized in distinctive ?80 nm ensembles able to undergo striking changes over time. Bidirectional PALM and single-molecule immunolabeling showed that dense nanodomains of PSD-95 were preferentially enriched in AMPA receptors more than NMDA receptors. Chronic suppression of activity triggered changes in PSD interior architecture that may help amplify synaptic plasticity. The observed clustered architecture of the PSD controlled the amplitude and variance of simulated postsynaptic currents, suggesting several ways in which PSD interior organization may regulate the strength and plasticity of neurotransmission.
| S-EPMC3668352 | biostudies-literature
Project description:Deprivation of peripheral nerve input by cochlear removal in young mice results in dramatic neuron death in the cochlear nucleus (CN). The same manipulation in older mice does not result in significant loss. The molecular basis of this critical period of vulnerability remains largely unknown. Here we identified genes regulated at early time points after cochlear removal at ages when neurons are vulnerable (postnatal day (P)7) or invulnerable (P21) to this challenge. Afferent deprivation regulated very different sets of genes at P7 and P21. These genes showed a variety of functions at both ages, but surprisingly there was no net increase in pro-apoptotic genes at P7. A large set of upregulated immune-related genes was identified at P21. Experiment Overall Design: Mice received unilateral cochlear removals. At 6, 12, 24, and 48 hours after surgery, the CN ipsilateral and contralateral were removed, and RNA isolated from separate pools of tissue for each replicate. Deafferented CN were compared to age-matched and time-matched contralateral, control CN to identify genes regulated by cochlear removal at age P7 and P21.
2008-06-13 | E-GEOD-5394 | biostudies-arrayexpress
Project description:Deprivation of peripheral nerve input by cochlear removal in young mice results in dramatic neuron death in the cochlear nucleus (CN). The same manipulation in older mice does not result in significant loss. The molecular basis of this critical period of vulnerability remains largely unknown. Here we identified genes regulated at early time points after cochlear removal at ages when neurons are vulnerable (postnatal day (P)7) or invulnerable (P21) to this challenge. Afferent deprivation regulated very different sets of genes at P7 and P21. These genes showed a variety of functions at both ages, but surprisingly there was no net increase in pro-apoptotic genes at P7. A large set of upregulated immune-related genes was identified at P21. Keywords: Time Course after Cochlear Removal, Age Comparison
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Project description:Significant changes in the expression of synaptic and inflammatory genes were observed early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration between afferent neurons and cochlear hair cells.
2020-09-14 | GSE130495 | GEO
Project description:In response to stimuli, the immediate early gene product Arc can acutely down-regulate synaptic strength by removing AMPA receptors (AMPARs) from synapses and thus regulate synaptic plasticity. How Arc, a scaffold protein, can specifically facilitate synaptic removal of AMPARs is unknown. We found that Arc directly antagonizes with PSD-95 in binding to TARPs, which are the auxiliary subunits of AMPARs. Arc, in a highly concentration-sensitive manner, acutely disperses TARPs from the postsynaptic density (PSD) condensate formed via phase separation. TARPs with the Ser residue in the "P-S-Y"-motif of its tail phosphorylated are completely refractory from being dispersed by Arc, suggesting that Arc cannot displace AMPARs from PSDs in active synapses. Conversely, strengthening the interaction between Arc and TARPs enhances Arc's capacity in weakening synapses. Thus, Arc can specifically and effectively modulate synaptic AMPAR clustering via modulating PSD phase separation. Our study further suggests that activity-dependent, bi-directional modulation of PSD condensate formation/dispersion represents a general regulatory mechanism for synaptic plasticity.
| S-EPMC9525282 | biostudies-literature
Project description:AMPA receptors (AMPARs) and their associations with auxiliary transmembrane proteins are bulky structures with large steric-exclusion volumes. Hence, self-crowding of AMPARs, depending on the local density, may affect their lateral diffusion in the postsynaptic membrane as well as in the highly crowded postsynaptic density (PSD) at excitatory synapses. Earlier theoretical studies considered only the roles of transmembrane obstacles and the AMPAR-binding submembranous scaffold proteins in shaping receptor diffusion within PSD. Using lattice model of diffusion, the present study investigates the additional impacts of self-crowding on the anomalousity and effective diffusion coefficient (Deff) of AMPAR diffusion. A recursive algorithm for avoiding false self-blocking during diffusion simulation is also proposed. The findings suggest that high density of AMPARs in the obstacle-free membrane itself engenders strongly anomalous diffusion and severe decline in Deff. Adding transmembrane obstacles to the membrane accentuates the anomalousity arising from self-crowding due to the reduced free diffusion space. Contrarily, enhanced AMPAR-scaffold binding, either through increase in binding strength or scaffold density or both, ameliorates the anomalousity resulting from self-crowding. However, binding has differential impacts on Deff depending on the receptor density. Increase in binding causes consistent decrease in Deff for low and moderate receptor density. For high density, binding increases Deff as long as it reduces anomalousity associated with intense self-crowding. Given a sufficiently strong binding condition when diffusion acquires normal behavior, further increase in binding causes decrease in Deff. Supporting earlier experimental observations are mentioned and implications of present findings to the experimental observations on AMPAR diffusion are also drawn.
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Project description:Precise alignment of pre- and postsynaptic elements optimizes the activation of glutamate receptors at excitatory synapses. Nonetheless, glutamate that diffuses out of the synaptic cleft can have actions at distant receptors, a mode of transmission called spillover. To uncover the extrasynaptic actions of glutamate, we localized AMPA receptors (AMPARs) mediating spillover transmission between climbing fibers and molecular layer interneurons in the cerebellar cortex. We found that climbing fiber spillover generates calcium transients mediated by Ca2+-permeable AMPARs at parallel fiber synapses. Spillover occludes parallel fiber synaptic currents, indicating that separate, independently regulated afferent pathways converge onto a common pool of AMPARs. Together these findings demonstrate a circuit motif wherein glutamate 'spill-in' from an unconnected afferent pathway co-opts synaptic receptors, allowing activation of postsynaptic AMPARs even when canonical glutamate release is suppressed.
| S-EPMC10229553 | biostudies-literature
Project description:Learning-related plasticity at excitatory synapses in the mammalian brain requires the trafficking of AMPA receptors and the growth of dendritic spines. However, the mechanisms that couple plasticity stimuli to the trafficking of postsynaptic cargo are poorly understood. Here we demonstrate that myosin Vb (MyoVb), a Ca2+-sensitive motor, conducts spine trafficking during long-term potentiation (LTP) of synaptic strength. Upon activation of NMDA receptors and corresponding Ca2+ influx, MyoVb associates with recycling endosomes (REs), triggering rapid spine recruitment of endosomes and local exocytosis in spines. Disruption of MyoVb or its interaction with the RE adaptor Rab11-FIP2 abolishes LTP-induced exocytosis from REs and prevents both AMPA receptor insertion and spine growth. Furthermore, induction of tight binding of MyoVb to actin using an acute chemical genetic strategy eradicates LTP in hippocampal slices. Thus, Ca2+-activated MyoVb captures and mobilizes REs for AMPA receptor insertion and spine growth, providing a mechanistic link between the induction and expression of postsynaptic plasticity.
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Project description:Pooled Immunoflourescent guided laser capture microdisection of calyceal vestibular primary afferent neurons (calretinin positive) and dimorphic-bouton vestibular primary afferent neurons (calretinin negative) were used for microarray expression profiling. Transcription analysis of each of these biologically diverse pools was completed.
2008-05-01 | E-MEXP-1560 | biostudies-arrayexpress