Neurons have adapted mechanisms to traffic RNA and protein into distant dendritic and axonal arbors. Taking a biochemical approach, we reveal that forebrain synaptic transcript accumulation shows ...overwhelmingly daily rhythms, with two-thirds of synaptic transcripts showing time-of-day-dependent abundance independent of oscillations in the soma. These transcripts formed two sharp temporal and functional clusters, with transcripts preceding dawn related to metabolism and translation and those anticipating dusk related to synaptic transmission. Characterization of the synaptic proteome around the clock demonstrates the functional relevance of temporal gating for synaptic processes and energy homeostasis. Unexpectedly, sleep deprivation completely abolished proteome but not transcript oscillations. Altogether, the emerging picture is one of a circadian anticipation of messenger RNA needs in the synapse followed by translation as demanded by sleep-wake cycles.
To investigate the effects of increasing axial load on cervical motor control. Surrogates of cervical motor control were active cervical range of motion (C-ROM) and joint position error (JPE) ...assessed in flexion, extension, lateroflexion and rotation directions in 49 healthy young men (mean age: 20.2 years). All measurements were executed with 0-, 1-, 2-, and 3-kg axial loads. Linear mixed models were used to assess the effects of axial loading and cervical movement-direction on C-ROM and JPE. Post-hoc analysis was performed to compare load levels. Axial loading (p = 0.045) and movement direction (p < 0.001) showed significant main effects on C-ROM as well as an interaction (p < 0.001). C-ROM significantly changed with 3-kg axial load by decreaseing extension (- 13.6%) and increasing lateroflexion (+ 9.9%). No significant main effect was observed of axial loading on JPE (p = 0.139). Cervical motor control is influenced by axial loading, which results in decreased C-ROM in extension and increased C-ROM lateroflexion direction.
Distinct plasticity mechanisms enable neurons to effectively process information also when facing global perturbations in network activity. In this issue of The EMBO Journal, Dubes et al (2022) ...provide a molecular mechanism whereby individual synapses during periods of chronic inactivity are “tagged” for future strengthening. These results lend further support to the idea that local, nonmultiplicative mechanisms play an important role in homeostatic synaptic plasticity as has been demonstrated for Hebbian‐like synaptic plasticity.
Recent work shows how global perturbations in network activity can also act locally to support future synaptic activity.
Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in ...vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75
) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the
gene in microglia or
S268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.
Synaptic scaling is a form of homeostatic plasticity which allows neurons to adjust their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires ...profound changes in gene expression, but the relative contribution of local and cell‐wide mechanisms is controversial. Here we perform a comprehensive multi‐omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. We uncover both highly compartment‐specific and correlating changes in the neuronal transcriptome and proteome. Whereas downregulation of crucial regulators of neuronal excitability occurs primarily in the somatic compartment, structural components of excitatory postsynapses are mostly downregulated in processes. Local inhibition of protein synthesis in processes during scaling is confirmed for candidate synaptic proteins. Motif analysis further suggests an important role for trans‐acting post‐transcriptional regulators, including RNA‐binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that, during synaptic scaling, compartmentalized gene expression changes might co‐exist with neuron‐wide mechanisms to allow synaptic computation and homeostasis.
Synopsis
Downscaling of excitatory synapses in response to high activity involves compartment‐specific changes in the neuron's transcriptome and proteome. This study supports the view that local gene regulation is important in both Hebbian and homeostatic forms of synaptic plasticity.
Hippocampal neurons grown on filter insets allow to study activity‐dependent changes in gene expression at the compartment level.
Different sets of genes are regulated in the somatic and process compartment of hippocampal neurons during synaptic downscaling.
The inhibition of genes encoding for excitatory synaptic proteins during downscaling occurs preferentially in the process compartment.
Motifs for RNA‐binding proteins and microRNAs are highly enriched in mRNAs specifically downregulated in the process compartment.
Downscaling of excitatory synapses in response to high activity involves compartment‐specific changes in the neuron's transcriptome and proteome. This study supports the view that local gene regulation is important in both Hebbian and homeostatic forms of synaptic plasticity.
Homeostatic synaptic depression (HSD) in excitatory neurons is a cell-autonomous mechanism which protects excitatory neurons from over-excitation as a consequence of chronic increases in network ...activity. In this process, excitatory synapses are weakened and eventually eliminated, as evidenced by a reduction in synaptic AMPA receptor expression and dendritic spine loss. Originally considered a global, cell-wide mechanism, local forms of regulation, such as the local control of mRNA translation in dendrites, are being increasingly recognized in HSD. Yet, identification of excitatory proteins whose local regulation is required for HSD is still limited. Here, we show that proline-rich protein 7/transmembrane adapter protein 3 (Prr7) down-regulation in dendrites of rat hippocampal neurons is necessary for HSD induced by chronic increase in network activity resulting from a blockade of inhibitory synaptic transmission by picrotoxin (PTX). We further identify two activity-regulated miRNAs, miR-329-3p and miR-495-3p, which inhibit Prr7 mRNA translation and are required for HSD. Moreover, we found that Prr7 knockdown reduces expression of the synaptic scaffolding protein SPAR, which is rescued by pharmacological inhibition of CDK5, indicating a role of Prr7 protein in the maintenance of excitatory synapses via protection of SPAR from degradation. Together, our findings highlight a novel HSD mechanism in which chronic activity leads to miR-329– and miR-495–mediated Prr7 reduction upstream of the CDK5-SPAR pathway.
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