Circadian protein TIMELESS regulates synaptic plasticity and memory by modulating cAMP signaling
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ABSTRACT:
PROVIDER: PRJNA858471 | ENA |
REPOSITORIES: ENA
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Project description:Regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of circadian genes on cellular and molecular mechanisms that influnce synaptic plasticity and cognitive function remain to be identified. Here, we show that conditional deletion of the circadian gene Timeless in the adult forebrain leads to an impairment in working and fear memory in mice. These cognitive phenotypes were accompanied with LTP attenuation of hippocampal Schaffer-collateral synapses. We discovered TIMELESS protein acts as a transcriptional factor regulating phosphodiesterase 4B (PDE4B) expression. Through Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and fine-tune synaptic plasticity. Our data provide insights into the neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.
2023-04-17 | GSE208149 | GEO
Project description:The regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of specific circadian genes on cellular and molecular mechanisms controlling synaptic plasticity and cognitive function remains elusive. Here, we show that the expression of the circadian protein TIMELESS displays circadian rhythmicity in the mammalian hippocampus. We identify TIMELESS as a chromatin-bound protein that targets synaptic-plasticity-related genes such as phosphodiesterase 4B (Pde4b). By promoting Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and influence synaptic plasticity. Conditional deletion of Timeless in the adult forebrain impairs working and contextual fear memory in mice. These cognitive phenotypes were accompanied by attenuation of hippocampal Schaffer-collateral synapse long-term potentiation. Together, these data establish a neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.
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Project description:Astrocytes play a key role in brain homeostasis and functions such as memory. Specifically, astrocytes express multiple receptors that transduce signals via the second messenger cAMP. However, the involvement of astrocytic cAMP in animal behavior and the underlying glial-neuronal interactions remains largely unknown. Here, we show that an increase in astrocytic cAMP is sufficient to induce synaptic plasticity and modulate memory. We developed a method to increase astrocytic cAMP levels in vivo using photoactivated adenylyl cyclase and found that increased cAMP in hippocampal astrocytes at different time points facilitated memory formation but interrupted memory retention via NMDA receptor-dependent plasticity. Furthermore, we found that the cAMP-induced modulation of memory was mediated by the astrocyte-neuron lactate shuttle. Thus, our study unveils a role of astrocytic cAMP in brain function by providing a tool to modulate astrocytic cAMP in vivo.
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Project description:Regions of DNA with the potential to form secondary structure pose a frequent and significant impediment to DNA replication that must be actively countered by cells in order to preserve genetic and epigenetic integrity. The fork protection complex (FPC), a conserved group of replisome-associated proteins, comprising Timeless, plays an important role in maintaining efficient replisome function. A previously unappreciated DNA binding domain in the C terminus of Timeless, which exhibits specificity towards G4 structures, acts in collaboration with the DDX11 helicase to ensure replication of G4 structures in vivo and maintenance of genetic and epigenetic stability. Using RNA-seq experiments, we show that (i) Timeless and DDX11 share common gene targets, (ii) the promoter of Timeless- and DDX11-dependent genes are enriched in G4 structures in the vicinity of their promoter and (iii) both Timeless and DDX11 share a common set of gene targets with the FANCJ helicase known to maintain epigenetic stability in the vicinity of G4 structures.
2020-07-01 | GSE139256 | GEO
Project description:Circadian rhythms are present across almost all species and affect several physiological and behavioral aspects of living organisms. The evolutionary advantage conferred by these rhythms could be their anticipatory properties. In the nervous system, anticipation is particularly interesting due to the spatiotemporal constraints derived by the highly compartmentalized neuronal structure. Previous work has confirmed that 900 genes are expressed in the mouse forebrain in robustly rhythmic fashion, and 180 transcripts are equally robustly circadian at the synapse. Interestingly, mRNAs are found in higher amounts at the end of the dark phase, and decrease exponentially during the first hours of light. This pattern resembles the “sawtooth” pattern of homeostatic sleep pressure. To further characterize this phenotype we propose to compare the synaptic transcriptome of sleep deprived mice to its control base line. This work would shed light into the emerging field of synaptic RNA transport and translation and its regulatory inputs. Hopefully, the results will yield to two different findings: the circadian and activity potential to regulate synaptic transport of RNA and the classification of transcripts deferentially regulated by both processes.
2019-02-28 | E-MTAB-7347 | biostudies-arrayexpress
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2020-01-18 | GSE143854 | GEO
Project description:The time of day strongly influences adaptive behaviors like long-term memory, but the correlating synaptic and molecular mechanisms remain unclear. The circadian clock comprises a canonical transcription-translation feedback loop (TTFL) strictly dependent on the BMAL1 transcription factor. We report that BMAL1 rhythmically localizes to hippocampal synapses in a manner dependent on its phosphorylation at Ser42 [pBMAL1(S42)]. pBMAL1(S42) regulates the autophosphorylation of synaptic CaMKIIα and circadian rhythms of CaMKIIα-dependent molecular interactions and LTP but not global rest/activity behavior. Therefore, our results suggest a model in which repurposing of the clock protein BMAL1 to synapses locally gates the circadian timing of plasticity.
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Project description:The lateral habenula (LHb) is an essential hub brain region modulating the monoamine system such as dopamine, serotonin. Hyperactivity of LHb has implications for psychiatric disorders such as depression, anxiety, and schizophrenia, which are commonly associated with social dysfunction. However, the role of LHb in social behavior has remained elusive. Here, we find that experiencing acute social isolation affects synaptic function in LHb and social behavior. After acute social isolation, long-term depression (LTD) in LHb is impaired and rescued by activating the 5-HT4 receptor (5-HT4R). Indeed, Htr4 expression in LHb is up-regulated following acute social isolation. Finally, acute social isolation enhances the social preference for familiars such as housing-mates to stranger conspecifics. Consistent with electrophysiological results, pharmacological activation of 5-HT4R in LHb restored innate social preference. These results suggest that acute social isolation influences social decisions with 5-HT4R-dependent synaptic modification in LHb.
2024-04-30 | GSE200082 | GEO
Project description:3′,5′-cyclic adenosine monophosphate (cAMP) is finally recognized as an essential signaling molecule in plants where cAMP-dependent processes include responses to hormones and environmental stimuli. To better understand the role of cAMP at the systems level, we have undertaken a phosphoproteomic analysis to elucidate the cAMP-dependent response of tobacco BY-2 cells. These cells overexpress a “sponge” that buffers intracellular cAMP level. The results show that, firstly, in vivo cAMP dampening profoundly affects the plant kinome and notably mitogen-activated protein kinases, receptor-like kinases and calcium-dependent protein kinases, thereby modulating the cellular responses at the systems level. Secondly, buffering cAMP levels also affects mRNA processing through the modulation of the phosphorylation status of several RNA-binding proteins with roles in splicing, including many SR proteins. Thirdly, cAMP-dependent phosphorylation targets appear to be conserved among plant species. Taken together, these findings are consistent with an ancient role of cAMP in mRNA processing and cellular programming and suggest that unperturbed cellular cAMP levels are essential for cellular homeostasis and signaling in plant cells.
2024-05-24 | PXD040912 | Pride
Project description:Homeostatic synaptic scaling is a compensatory mechanism that allows adjustment of the strength of synaptic connections up or down in response to changes in input to maintain global network stability. To characterize the molecular changes on the level of protein modification that contribute to synaptic scaling, we examined changes of the proteome and phosphoproteome in response to activity manipulation. For this purpose, we pharmacologically induced up- or down-scaling in primary cultured cortical neurons for different time spans ranging from minutes (5 min, 15 min) up to one day. Temporal snapshots of the neuronal proteome and phosphoproteome were obtained using high-resolution LC-MS/MS analyses. Our data cover 45,395 phosphorylated peptide species that map to 26,642 unique phosphorylation sites. Activity manipulation elicited significant regulation of 3,382 phosphorylation events on proteins predominantly located at the synaptic compartment or involved in organization of the cytoskeleton. With respect to the temporal regulation, we discovered that phosphomodulation during scaling was not only achieved by time-limited phosphorylation, but for a quarter of initial sites also by persistent regulation. Persistence in phosphorylation was associated with reciprocity in the sign of its regulation, reflecting the two different scaling polarities.
2021-08-12 | PXD021834 | Pride