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Neddylation regulate the development of glutamatergic neurons

ABSTRACT: The development and function of synapses is orchestrated by a plethora of regulatory mechanisms hierarchically controlling gene expression to protein function. Expanding the proteome, protein post-translational modification are additional key events in neu-rons. In such context, the modification of protein with ubiquitin-like modifier (Ubls) such as the SUMOs, but also other Ubls like NEDD8, have been revealed as major steps in regulating neuronal development and synaptic transmission, either by directly acting lo-cally at synapse or via nuclear-mediated mechanism and the regulation of gene expres-sion. In the present work, we focus on NEDD8 and characterized neuronal morphology, synap-tic transmission and the transcriptional landscape of NEDD8 deficient hippocampal au-taptic neurons. While we observed no major alteration in neuronal morphology, NEDD8-deficient neurons have a decreased pool of ready-releasable synaptic vesicles. This de-fect was likely caused by an imbalance in the expression of vGLUT1/vGLUT2 and de-creased endophilin1 level. Indeed, transcriptome analysis revealed profound defects in the expression of key transcriptional regulators determining glutamatergic neurodevel-opment, indicating that NEDD8 foster the expression of glutamatergic cell fate.

ORGANISM(S): Mus musculus

PROVIDER: GSE269898 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Background Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory. Here, we investigated whether CPEB2 regulates axonal translation to support presynaptic plasticity. Methods Behavioral and electrophysiological assessments were conducted in mice with pan neuron/glia- or AQ2glutamatergic neuron-specific knockout of CPEB2. Hippocampal Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 pathways were electro-recorded to monitor synaptic transmission and LTP evoked by 4 trains of high-frequency stimulation. RNA immunoprecipitation, coupled with bioinformatics analysis, were used to unveil CPEB2-binding axonal RNA candidates associated with learning, which were further validated by Western blotting and luciferase reporter assays. Adeno-associated viruses expressing Cre recombinase were stereotaxically delivered to the pre- or post-synaptic region of the TA circuit to ablate Cpeb2 for further electrophysiological investigation. Biochemically isolated synaptosomes and axotomized neurons cultured on a microfluidic platform were applied to measure axonal protein synthesis and FM4-64FX-loaded synaptic vesicles. Results Electrophysiological analysis of hippocampal CA1 neurons detected abnormal excitability and vesicle release probability in CPEB2-depleted SC and TA afferents, so we cross-compared the CPEB2-immunoprecipitated transcriptome with a learning-induced axonal translatome in the adult cortex to identify axonal targets possibly regulated by CPEB2. We validated that Slc17a6, encoding vesicular glutamate transporter 2 (VGLUT2), is translationally upregulated by CPEB2. Conditional knockout of CPEB2 in VGLUT2-expressing glutamatergic neurons impaired consolidation of hippocampus-dependent memory in mice. Presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated TA afferents was sufficient to attenuate protein synthesis-dependent LTP. Moreover, blocking activity-induced axonal Slc17a6 translation by CPEB2 deficiency or cycloheximide diminished the releasable pool of VGLUT2-containing synaptic vesicles. Conclusions We identified 272 CPEB2-binding transcripts with altered axonal translation post-learning and established a causal link between CPEB2-driven axonal synthesis of VGLUT2 and presynaptic translation-dependent LTP. These findings extend our understanding of memory-related translational control mechanisms in the presynaptic compartment.

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Neddylation regulate the development of glutamatergic neurons

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