Peripheral Substance P induces deficits in hippocampal synaptic plasticity and memory
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE301993 | GEO | 2025/08/20
REPOSITORIES: GEO
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Project description:Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive.This study investigates the DNA-methylation levels of promoters and CpG-islands of LTP-associated genes identified from Maag et al. 2015 (DOI: 10.3389/fnins.2015.00351) (See E-MTAB-3375).
2017-03-16 | E-MTAB-4919 | biostudies-arrayexpress
Project description:Experience-dependent learning depends on synaptic plasticity. Recent findings show that effective integration of novel salient information requires coordinated processes of homo- and hetero- synaptic plasticity onto neighboring dendritic branches. In this work, we hypothesized that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to this mechanism. We show that clusters of the peri-synaptic ECM proteoglycans, containing 6- and 2,6-sulfated chondroitin sulfates recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. CS56 co-immunoprecipitation of synaptosomal proteins identified several CS56-carrying/binding synaptic molecules that are implicated in Ca2+ signaling, vesicles cycling and AMPA-receptor exocytosis, thus suggesting their pivotal role in long-term potentiation (LTP). Finally, we demonstrated that the attenuation of CS56 glycoepitopes in the CA1 hippocampal region, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in adult mice. These findings show that specific ECM glycans regulates the molecular mechanisms underlying induction and consolidation of synaptic plasticity, confirming that experience-dependent refinement of the brain ECM plays a critical role in learning and memory.
2024-05-10 | PXD047129 | Pride
Project description:Experience-dependent learning depends on synaptic plasticity. Recent findings show that effective integration of novel salient information requires coordinated processes of homo- and hetero- synaptic plasticity onto neighboring dendritic branches. In this work, we hypothesized that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to this mechanism. We show that clusters of the peri-synaptic ECM proteoglycans, containing 6- and 2,6-sulfated chondroitin sulfates recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. CS56 co-immunoprecipitation of synaptosomal proteins identified several CS56-carrying/binding synaptic molecules that are implicated in Ca2+ signaling, vesicles cycling and AMPA-receptor exocytosis, thus suggesting their pivotal role in long-term potentiation (LTP). Finally, we demonstrated that the attenuation of CS56 glycoepitopes in the CA1 hippocampal region, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in adult mice. These findings show that specific ECM glycans regulates the molecular mechanisms underlying induction and consolidation of synaptic plasticity, confirming that experience-dependent refinement of the brain ECM plays a critical role in learning and memory.
2024-05-10 | PXD050008 | Pride
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.
2024-07-08 | GSE208738 | GEO
Project description:Myotonic dystrophy type I (DM1) patients demonstrate visuospatial dysfunction and impaired performance in tasks requiring recognition or memory of figures and objects. In DM1, CUG expansion RNAs inactivate the Muscleblind-like (MBNL) proteins. We show that constitutive Mbnl2 inactivation in Mbnl2ΔE2/ΔE2 mice, selectively impairs object recognition memory in the novel object recognition test. When exploring the context of a novel arena in which the objects are later encountered, the Mbnl2ΔE2/ΔE2 dorsal hippocampus responds with a lack of enrichment for learning and memory related pathways, mounting instead transcriptome alterations predicted to impair growth and neuron viability. In Mbnl2ΔE2/ΔE2 mice, saturation effects may prevent deployment of a functionally relevant transcriptome response during novel context exploration. Post-novel context exploration alterations in genes implicated in tauopathy and dementia are observed in the Mbnl2ΔE2/ΔE2 dorsal hippocampus. Thus MBNL2 inactivation in DM1 patients may alter novel context processing in the dorsal hippocampus and impair object recognition memory.
2023-05-22 | GSE226191 | GEO
Project description:Neurons utilize glucose to generate adenosine triphosphate (ATP) essential for their survival, excitability and synaptic signaling, as well as initiating changes in neuronal structure and function. Defects in oxidative metabolism and mitochondria functions are also associated with aging and diverse human neurological diseases1-4. While neurons are known to adapt their metabolism to meet the increased energy demands of complex behaviors such as learning and memory, the molecular underpinnings regulating this process remain poorly understood4-6. Here we show that the orphan nuclear receptor estrogen related receptor gamma (ERRγ) becomes highly expressed during retinoic-acid induced neurogenesis and is widely expressed in neuronal nuclei throughout the brain. Mechanistically, we show that ERRγ directly orchestrates the expression of networks of genes involved in mitochondrial oxidative phosphorylation and energy generation in neurons. The importance of this regulation is evidenced by decreased adaptive metabolic capacity in cultured neurons lacking ERRγ, and reduced long-term potentiation (LTP) in ERRγ-/- hippocampal slices. Notably, the defect in LTP was rescued by the metabolic intermediate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ exhibit defects in spatial learning and memory. These findings implicate ERRγ in the metabolic adaptations required for long-term memory formation. We used ChIP-Seq analysis to determine the genome-wide binding of ERRγ in neurons derived from ES cells.
2015-09-03 | E-GEOD-47134 | biostudies-arrayexpress
Project description:N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammalian messenger RNAs (mRNAs). While m6A has been shown to mark groups of mRNAs for coordinated degradation in various physiological processes, the relevance of m6A in affecting translation remains to be determined in intact biological systems in vivo. Here we show that, through its reader protein Ythdf1, m6A promotes a pulse of protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory processes. Mice with genetic deletion of the Ythdf1 gene (Ythdf1-/-) exhibit learning and memory defects, as well as impaired hippocampal synaptic transmission and long-term potentiation (LTP). Selective re-expression of Ythdf1 in the hippocampus of adult Ythdf1-/- mice fully rescues the behavioral and synaptic defects, while hippocampus-specific knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency in adult mice. At the molecular level, transcriptome-wide mapping of m6A sites and RNA binding sites of Ythdf1 on hippocampal mRNAs using crosslinking immunoprecipitation followed by high-throughput sequencing (CLIP-seq) uncovered key neuronal genes, including those involved in synaptic transmission and long-term potentiation. Nascent protein labelling and tether reporter assays in cultured hippocampal neurons revealed that Ythdf1 is critical for initiating a pulse of protein synthesis of target transcripts in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.
2018-08-17 | GSE106607 | GEO
Project description:Neurons utilize glucose to generate adenosine triphosphate (ATP) essential for their survival, excitability and synaptic signaling, as well as initiating changes in neuronal structure and function. Defects in oxidative metabolism and mitochondria functions are also associated with aging and diverse human neurological diseases1-4. While neurons are known to adapt their metabolism to meet the increased energy demands of complex behaviors such as learning and memory, the molecular underpinnings regulating this process remain poorly understood4-6. Here we show that the orphan nuclear receptor estrogen related receptor gamma (ERRγ) becomes highly expressed during retinoic-acid induced neurogenesis and is widely expressed in neuronal nuclei throughout the brain. Mechanistically, we show that ERRγ directly orchestrates the expression of networks of genes involved in mitochondrial oxidative phosphorylation and energy generation in neurons. The importance of this regulation is evidenced by decreased adaptive metabolic capacity in cultured neurons lacking ERRγ, and reduced long-term potentiation (LTP) in ERRγ-/- hippocampal slices. Notably, the defect in LTP was rescued by the metabolic intermediate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ exhibit defects in spatial learning and memory. These findings implicate ERRγ in the metabolic adaptations required for long-term memory formation. We used microarray analysis to compare the genome-wide gene expression changes between wild type (WT) and ERRγ-/- P0 cerebral cortex as it contains mainly neuronal lineage at this stage compared to adult cortex.
2015-09-03 | E-GEOD-47133 | biostudies-arrayexpress
Project description:Synaptic plasticity underlying long-term memory is associated with the generation of saturated free fatty acids (sFFAs), in particularly myristic acid, from membrane phospholipids via the phospholipase A1 isoform DDHD2. However, the mechanism through which myristic acid contributes to synaptic plasticity remains elusive. Here, we demonstrate that DDHD2-derived myristic acid is rapidly converted to myristoyl CoA, which serves as substrate for N-myristoyl transferases (NMT1/2) to drive post-translational lysine myristoylation of synaptic proteins. Chemically induced long-term potentiation (cLTP) in cortical neurons increases both sFFAs and their CoA conjugates, predominantly myristoyl CoA, a response blocked by the DDHD2 inhibitor KLH-45. Inhibition of DDHD2 (KLH-45) or NMT1/2 (IMP-1088) also disrupts cLTP-induced proteomic changes, impairs dendritic spine remodeling, and prevents LTP in hippocampal slices. Instrumental conditioning also drives proteomic change in the hippocampus, that are abolished in learning-deficient DDHD2-/- mice. Key synaptic proteins, including NMDA receptor subunit GluN1, MAP2, and GAS7, fail to undergo learning-induced changes, effectively linking DDHD2 function to learning-dependent proteome remodeling. Our findings reveal that de novo lysine myristoylation acts to mediate synaptic plasticity and memory formation.
2025-04-22 | PXD061811 | Pride
Project description:Here we report bulk RNA transcriptomes of cortical brains from transgenic mice from Grin1-exon5 constitutive vs. Grin1-exon5 knockout mice. Physiologically, Grin1-exon5 positive mice have reduced hippocampal LTP (vs. WT) and are learning and memory (vs. WT) impaired compared to Grin1-exon5 negative mice that have heightened LTP (compared to WT) and better learning and memory (compared to WT).
2019-10-31 | GSE136983 | GEO