A Conserved Role for Drosophila Neuroglian and Human L1-CAM in Central-Synapse Formation
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Excitatory synapse
Regulatory functions of lncRNAs in neurons have been majorly limited to the nucleus. The identity of synaptic lncRNAs and their functional role associated with synapse development and memory are poorly understood. We employed RNA-seq analysis of synaptoneurosomes to identify 94 synapse-enriched lncRNAs from the mouse hippocampus. We find Pvt1 to be a specific regulator of excitatory, but not inhibitory, synapse development in vivo. RNA-Seq from Pvt1 knockdown neurons identified down-regulated transcripts encoding pre- and post-synaptic proteins influencing synapse formation. This observation is congruent with reduction in mEPSC amplitude and frequency. We find a synapse-centric role for SynLAMP which is specifically transported to the synaptic compartment upon contextual fear conditioning (CFC) and regulate activity-dependent dendritic translation. CFC promotes the interaction between SynLAMP and the translation repressor FUS, indicating SynLAMP to be a molecular decoy. SynLAMP RNAi partially occludes fear memory, suggesting an input-specific role of lncRNAs at the synapse.
Excitatory synapse
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The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory–inhibitory balance.
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Excitatory synapse
Silent synapse
Gephyrin
Synapse formation
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Agrin
Excitatory synapse
Ribbon synapse
Synaptic pharmacology
Synaptic cleft
Silent synapse
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Synaptic cleft
Neuromodulation
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The Ubiquitin Proteasome System (UPS) has been shown to regulate neuronal development and synapse formation. Activity-dependent regulation of E3 ligase, a component of the UPS that targets specific proteins for proteasome-mediated degradation, is emerging as a pivotal player for the establishment of functional synapses. Here, we identified TRIM47 as a developmentally regulated E3 ligase that is expressed in rat hippocampus during the temporal window of synapse formation. We have demonstrated that the expression of TRIM47 is regulated by the glutamate-induced synaptic activity of hippocampal neurons in culture. In addition, the activity-dependent enhancement of TRIM47 expression is recapitulated following the object location test, a hippocampus-dependent spatial memory paradigm. We observed that this enhancement of TRIM47 expression requires NMDA receptor activation. The knockdown of TRIM47 leads to an enhancement of spine density without affecting dendritic complexity. Furthermore, we observed an increase in excitatory synapse development upon loss of TRIM47 function. Comprehensively, our study identified an activity-regulated E3 ligase that drives excitatory synapse formation in hippocampal neurons.
Excitatory synapse
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Amino acid substitution
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