Changes in presynaptic gene expression during homeostatic compensation at a central synapse
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB42857 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Homeostatic matching of pre- and postsynaptic function has been observed in many species and neural structures, but whether transcriptional changes contribute to this form of trans-synaptic coordination remains unknown. To identify genes whose expression is altered in presynaptic neurons as a result of perturbing postsynaptic excitability, we applied a transcriptomics-friendly, temperature-inducible Kir2.1-based activity clamp at the first synaptic relay of the Drosophila olfactory system, a central synapse known to exhibit trans-synaptic homeostatic matching. Twelve hours after adult-onset suppression of activity in postsynaptic antennal lobe projection neurons of males and females, we detected changes in the expression of many genes in the third antennal segment, which houses the somata of presynaptic olfactory receptor neurons. These changes affected genes with roles in synaptic vesicle release and synaptic remodeling, including several implicated in homeostatic plasticity at the neuromuscular junction. At 48 h and beyond, the transcriptional landscape tilted toward protein synthesis, folding, and degradation; energy metabolism; and cellular stress defenses, indicating that the system had been pushed to its homeostatic limits. Our analysis suggests that similar homeostatic machinery operates at peripheral and central synapses and identifies many of its components. The presynaptic transcriptional response to genetically targeted postsynaptic perturbations could be exploited for the construction of novel connectivity tracing tools.SIGNIFICANCE STATEMENT Homeostatic feedback mechanisms adjust intrinsic and synaptic properties of neurons to keep their average activity levels constant. We show that, at a central synapse in the fruit fly brain, these mechanisms include changes in presynaptic gene expression that are instructed by an abrupt loss of postsynaptic excitability. The trans-synaptically regulated genes have roles in synaptic vesicle release and synapse remodeling; protein synthesis, folding, and degradation; and energy metabolism. Our study establishes a role for transcriptional changes in homeostatic synaptic plasticity, points to mechanistic commonalities between peripheral and central synapses, and potentially opens new opportunities for the development of connectivity-based gene expression systems.
| S-EPMC8026347 | biostudies-literature
Project description:We profiled the transcriptomic changes that occur in the Drosophila third antennal segment after silencing the second order olfactory neurons in the antennal lobe with Kir2.1 (EH1). A non-conducting variant of Kir2.1 (Kir2.1-nc or EH2) served as our control.
2021-02-14 | E-MTAB-10065 | biostudies-arrayexpress
Project description:In homeostatic scaling, the cellular mechanisms that detect the offset from the set-point, the duration of the offset and implement a cellular response are not well-understood. To understand the time-dependent dynamics,we manipulated activity for 2 hrs to induce the process of up or down-scaling and metabolically labelled nascent proteins using BONCAT. We analyzed the newly synthesized proteins that exhibited significant increases or decreases in expression in response to activity manipulations and identified 168 proteins. Then, to obtain a temporal trajectory of the cellular response, we compared the proteins synthesized within 2 and 24 hrs of an activity manipulation. Surprisingly, there was little overlap in the significantly regulated newly synthesized proteins identified in the early- and late-response datasets. There was, however, overlap in the functional categories that are modulated early and late, indicating that within protein function groups, different proteomic choices can be made to effect early and late homeostatic responses.
2018-02-16 | PXD008271 | Pride
Project description:Structural, functional, and molecular reorganization of denervated neural networks is often observed in neurological conditions. The loss of input is accompanied by homeostatic synaptic adaptations, which can affect the reorganization of denervated networks. However, a major challenge of denervation-induced homeostatic plasticity operating in complex neural networks is the specialization of neuronal inputs. Therefore, it remains unclear whether neurons respond similarly to the loss of distinct inputs. Here, we used in vitro entorhinal cortex lesion (ECL) and Schaffer collateral lesion (SCL) in mouse organotypic entorhino-hippocampal tissue cultures of either sex, and studied denervation-induced plasticity of CA1 pyramidal neurons. We observed accumulation of microglia, degeneration of presynaptic buttons and a reduction in dendritic spine numbers in the denervated layers three days after SCL and ECL, respectively. Transcriptome analysis of the CA1 region showed complex changes in differential gene expression following SCL and ECL compared to non-lesioned controls. An enrichment of differentially expressed synapse-related genes was observed specifically after ECL. Consistent with this finding, denervation-induced homeostatic plasticity of excitatory synapses was observed three days after ECL but not after SCL. Chemogenetic silencing of the EC but not CA3 confirmed the pathway-specific induction of homeostatic synaptic plasticity in CA1. Moreover, increased RNA oxidation was observed after SCL and ECL. These results reveal important commonalities and differences of distinct pathway lesions, and demonstrate a pathway-specific induction of denervation-induced homeostatic synaptic plasticity.
2023-02-10 | GSE223096 | GEO
Project description:Synapses are asymmetric junctions between presynaptic and postsynaptic neurons that mediate information transfer in the brain. The proper formation of functional synapses is crucial for synaptic transmission and brain function. However, how neurons initially recognize each other to form synapses remain to be elucidated. Here, we performed single-cell RNA sequencing of the cultured hippocampal cells on the critical time points during synapse development. . We first built comprehensive single-cell transcriptomic atlas of hippocampus undergoing synapse formation. Furthermore, we focused on neurons, and systematically analyzed temporal dynamic functional transcription factors hubs.. We identified that transcription factors, such as EGR family genes, AP-1 family genes, NeuroD family genes, NF1 family genes, may act as key regulators of synapse formation. Besides, we provided the resources of increased membrane and secretory proteins associated with synapse formation, which including previously reported synapse formation genes, Nlgn3, Nectin1, Dag1, Snap25, and the newly identified potential genes, Tmem65, Grm5, Olfm1, Timp3. Finally, we analyzed the changes of cell communication signaling pathways in neurons before and after synapse formation, and identified several important signaling pathways, including NRXN, NCAM, BMP, NEGR, and so on. Collectively, our work provided a holistic view of the molecular dynamics of the hippocampal synapse formation.
2023-12-30 | GSE212792 | GEO
Project description:Homeostatic scaling is a global form of synaptic plasticity used by neurons to adjust overall synaptic weight and maintain neuronal firing rates while protecting information coding. While homeostatic scaling has been demonstrated in vitro, a clear physiological function of this plasticity type has not been defined. Sleep is an essential process that modifies synapses to support cognitive functions such as learning and memory. Evidence suggests that information coding during wake drives synapse strengthening which is offset by weakening of synapses during sleep .Here we use biochemical fractionation, proteomics and in vivo two-photon imaging to characterize wide-spread changes in synapse composition in mice through the wake/sleep cycle. We find that during the sleep phase, synapses are weakened through dephosphorylation and removal of synaptic AMPA-type glutamate receptors (AMPARs) driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors (mGluR1/5), consistent with known mechanisms of homeostatic scaling-down in vitro. Further, we find that these changes are important in the consolidation of contextual memories. While Homer1a gene expression is driven by neuronal activity during wake, Homer1a protein targeting to synapses serves as an integrator of arousal and sleep need through signaling by the wake-promoting neuromodulator noradrenaline (NA) and sleep-promoting modulator adenosine. During sleep or periods of increased sleep need Homer1a enters synapses where it remodels mGluR1/5 signaling complexes to promote AMPAR removal. Thus, we have characterized widespread changes occurring at synapses through the wake/sleep cycle and demonstrated that known mechanisms of homeostatic scaling-down previously demonstrated only in vitro are active in the brain during sleep to remodel synapses, contributing to memory consolidation.
2017-02-13 | PXD004537 | Pride
Project description:We measured gene expression in two isogenic Drosophila lines heterozygous for long deletions. We find that a majority of genes are at least partially compensated at transcription for ½-fold dosage. The degree of compensation does not vary among functional classes of genes. Compensation for deletions is stronger for highly expressed genes than for genes with low expression level. In contrast, the degree of compensation for duplications observed in Gupta et al, 2006, (J. of Biology 5, 3) data for heterozygotes for a duplication is stronger for weakly expressed genes. Thus, transcriptional compensation appears to be based on general regulatory mechanisms that insure high levels of transcription some genes and low transcription levels of other genes, instead of precise maintenance of a particular homeostatic expression level. Given the ubiquity of transcriptional compensation, dominance of wild-type alleles may be at least partially caused by of the regulation at transcription level. Keywords: Genome-wise dosage compensation study
2009-04-03 | GSE14799 | GEO
Project description:Neural circuits utilize a host of homeostatic plasticity mechanisms, including synaptic scaling, to maintain stability in circuits undergoing experience-dependent remodeling necessary for information processing. During synaptic scaling, compensatory adaptations in synaptic strength are induced after chronic manipulations in neuronal firing, but our understanding of this process is largely limited to its initial induction. How these homeostatic synaptic adaptations evolve when activity renormalizes and their impact on subsequent homeostatic compensation are both poorly understood. To examine these issues, we investigated whether a previous history of homeostatic scaling in networks of cultured hippocampal neurons altered their subsequent homeostatic responses to chronic activity manipulations. Unexpectedly, we found that a history of synaptic scaling strongly suppressed future scaling to the same, and even opposite, activity challenges. This history-dependent suppression was specific for future homeostatic compensation, as networks with a prior scaling history showed no deficits in the chemical induction of long-term potentiation (cLTP), a Hebbian form of synaptic plasticity. Hippocampal neurons with a prior scaling history exhibited normal engagement of activity-dependent signaling during subsequent activity challenges (as assessed by examination of the ERK/MAPK pathway) but demonstrated widespread alterations in activity-dependent transcriptional
2024-09-01 | GSE180993 | GEO
Project description:Animal behavior is remarkably robust despite constant changes in neural activity. Homeostatic plasticity stabilizes central nervous system (CNS) function on time scales of hours to days. If and how CNS function is stabilized on more rapid time scales remains unknown. Here, we discovered that mossy fiber synapses in the mouse cerebellum homeostatically control synaptic efficacy within minutes after pharmacological glutamate receptor impairment. This rapid form of homeostatic plasticity is expressed presynaptically. We show that modulations of readily releasable vesicle pool size and release probability normalize synaptic strength in a hierarchical fashion upon acute pharmacological and prolonged genetic receptor perturbation. Presynaptic membrane capacitance measurements directly demonstrate regulation of vesicle pool size upon receptor impairment. Moreover, presynaptic voltage-clamp analysis revealed increased Ca2+-current density under specific experimental conditions. Thus, homeostatic modulation of presynaptic exocytosis through specific mechanisms stabilizes synaptic transmission in a CNS circuit on time scales ranging from minutes to months. Rapid presynaptic homeostatic plasticity may ensure stable neural circuit function in light of rapid activity-dependent plasticity.
| S-EPMC6876255 | biostudies-literature
Project description:Neuronal synapse formation and remodeling is essential to central nervous system (CNS) development and is dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this impacts CNS synapses is largely unknown. Here we show that the IL-1 family cytokine Interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development.
2018-02-05 | GSE109353 | GEO