NMDAR mediated dynamic changes in m6A inversely correlates with neuronal translation.
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ABSTRACT:
SUBMITTER: Gowda NKC
PROVIDER: S-EPMC9256623 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:NMDARs and ASIC1a both exist in central synapses and mediate important physiological and pathological conditions, but the functional relationship between them is unclear. Here we report several novel findings that may shed light on the functional relationship between these two ion channels in the excitatory postsynaptic membrane of mouse hippocampus. Firstly, NMDAR activation induced by either NMDA or OGD led to increased [Ca(2+)](i)and greater apoptotic and necrotic cell deaths in cultured hippocampal neurons; these cell deaths were prevented by application of NMDAR antagonists. Secondly, ASIC1a activation induced by pH 6.0 extracellular solution (ECS) showed similar increases in apoptotic and necrotic cell deaths; these cell deaths were prevented by ASIC1a antagonists, and also by NMDAR antagonists. Since increased [Ca(2+)](i)leads to increased cell deaths and since NMDAR exhibits much greater calcium permeability than ASIC1a, these data suggest that ASIC1a-induced neuronal death is mediated through activation of NMDARs. Thirdly, treatment of hippocampal cultures with both NMDA and acidic ECS induced greater degrees of cell deaths than either NMDA or acidic ECS treatment alone. These results suggest that ASIC1a activation up-regulates NMDAR function. Additional data supporting the functional relationship between ASIC1a and NMDAR are found in our electrophysiology experiments in hippocampal slices, where stimulation of ASIC1a induced a marked increase in NMDAR EPSC amplitude, and inhibition of ASIC1a resulted in a decrease in NMDAR EPSC amplitude. In summary, we present evidence that ASIC1a activity facilitates NMDAR function and exacerbates NMDAR-mediated neuronal death in pathological conditions. These findings are invaluable to the search for novel therapeutic targets in the treatment of brain ischemia.
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Project description:Protein synthesis is crucial for maintaining synaptic plasticity and synaptic signalling. Here we have attempted to understand the role of RNA binding proteins, Fragile X Mental Retardation Protein (FMRP) and Moloney Leukemia Virus 10 (MOV10) protein in N-Methyl-D-Aspartate Receptor (NMDAR) mediated translation regulation. We show that FMRP is required for translation downstream of NMDAR stimulation and MOV10 is the key specificity factor in this process. In rat cortical synaptoneurosomes, MOV10 in association with FMRP and Argonaute 2 (AGO2) forms the inhibitory complex on a subset of NMDAR responsive mRNAs. On NMDAR stimulation, MOV10 dissociates from AGO2 and promotes the translation of its target mRNAs. FMRP is required to form MOV10-AGO2 inhibitory complex and to promote translation of MOV10 associated mRNAs. Phosphorylation of FMRP appears to be the potential switch for NMDAR mediated translation and in the absence of FMRP, the distinct translation response to NMDAR stimulation is lost. Thus, FMRP and MOV10 have an important regulatory role in NMDAR mediated translation at the synapse.
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Project description:A dendritic spine is a small structure on the dendrites of a neuron that processes input timing information from other neurons. Tens of thousands of spines are present on a neuron. Why are spines so small and many? We addressed this issue by using the stochastic simulation model of N-methyl-D-aspartate receptor (NMDAR)-mediated Ca2+ increase. NMDAR-mediated Ca2+ increase codes the input timing information between prespiking and postspiking. We examined how much the input timing information is encoded by Ca2+ increase against presynaptic fluctuation. We found that the input timing information encoded in the cell volume (103?m3) largely decreases against the presynaptic fluctuation, whereas that in the spine volume (10-1?m3) slightly decreases. Therefore, the input timing information encoded in the spine volume is more robust against presynaptic fluctuation than that in the cell volume. We further examined the mechanism of the robust information transfer in the spine volume. We demonstrated that the condition for the robustness is that the stochastic NMDAR-mediated Ca2+ increase (intrinsic noise) becomes much larger than the presynaptic fluctuation (extrinsic noise). When the presynaptic fluctuation is large, the condition is satisfied in the spine volume but not in the cell volume. Moreover, we compared the input timing information encoded in many small spines with that encoded in a single large spine. We found that the input timing information encoded in many small spines are larger than that in a single large spine when presynaptic fluctuation is large because of their robustness. Thus, robustness is a functional reason why dendritic spines are so small and many.
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Project description:Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS.
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Project description:Backgroundβ Amyloid (Aβ)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer's disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N-methyl-D-aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity.MethodsWhole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-β-benzyloxyaspartic acid (TBOA) or human Aβ1-42 peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma.ResultsBlocking glutamate uptake with either TBOA or the human Aβ1-42 peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aβ1-42-induced somatic potentiation and neuronal hyperactivity.ConclusionsThe somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.
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Project description:SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in SYNGAP1 (SYNGAP1 -/+) has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of Syngap1 -/+. However, the molecular mechanism behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in Syngap1 -/+ mice. Our results demonstrate that FMRP interacts with and regulates the translation of Syngap1 mRNA. We further show reduced Fmr1 translation leads to decreased FMRP level during development in Syngap1 -/+ which results in an increase in Syngap1 translation. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA Receptor (NMDAR)-mediated signaling. In this study, we propose a cross-talk between FMRP and SYNGAP1 mediated signaling which can also explain the compensatory effect of impaired signaling observed in Syngap1 -/+ mice.
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