Reciprocal Interaction of Dendrite Geometry and Nuclear Calcium–VEGFD Signaling Gates Memory Consolidation and Extinction

Hemstedt, Thekla J.; Bengtson, C. Peter; Ramírez, Omar; Oliveira, Ana M.M.; Bading, Hilmar

doi:10.1523/jneurosci.2345-16.2017

Cited by 18 publications

(27 citation statements)

References 35 publications

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“…Next, we determined the effect of Dnmt3a2 overexpression within DG ensembles on cognitive function. Before performing the memory test, we habituated the mice to the experimental room and experimenter at a time point for which viral expression was confirmed to be almost undetectable 14,20 (Fig. 1c).…”

Section: Resultsmentioning

confidence: 99%

“…Two days after the stereotaxic surgery, mice were habituated to the experimenter and experiment room by gentle handling for 5 days, 2 min per mouse. Habituation was performed in the first week of rAAV delivery, when the rAAV expression is almost undetectable 14,20 , to minimize the habituation-induced expression of Dnmt3a2. Two weeks after the last handling day, CFC or spatial object learning was performed 57 .…”

Section: Methodsmentioning

confidence: 99%

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Neuronal ensemble-specific DNA methylation strengthens engram stability

et al. 2020

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Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Neuronal ensemble-specific DNA methylation strengthens engram stability

et al. 2020

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“…In contrast to HDAC4, morphometric analyses revealed that overexpression of HDAC3 or HDAC11 had no effect on the dendritic length (lacZ 2499 µm ± 144 µm; HDAC3 2681 µm ± 134 µm; HDAC11 2838 µm ± 115 µm; HDAC4 regulates the expression of the neuronal morphology regulator, VEGFD -Our previous work identified Vascular Endothelial Growth Factor D (VEGFD) as a key regulator of neuronal morphology (12)(13)(14). Similar to class IIa HDACs shuttling, VEGFD expression is controlled by nuclear calcium signaling and affected by the calcium buffering capacity of the nucleus (13,14).…”

Section: Resultsmentioning

confidence: 99%

“…VEGFD is a key regulator of proper connectivity -VEGFD is a key factor for the maintenance of mature dendritic structure of pyramidal neurons (13,14), and as such crucial for memory formation as well as consolidation and extinction of fear memory (12,13). Several disorders of the nervous system are characterized by both aberrations of morphology and HDAC4 nuclear localization.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear calcium also controls the expression of Vascular Endothelial Growth Factor D (VEGFD), a key factor for the maintenance of proper dendritic arborization (12)(13)(14). Mechanistically, nuclear calcium influences transcription both by regulating the activity of transcription factors and by modulating epigenetic processes, which includes induction of expression of DNA methyltransferases (15) and the nucleocytoplasmic shuttling of class IIa HDACs (10).…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D

Litke¹,

Bading²,

Mauceri³

2018

Journal of Biological Chemistry

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Nucleo-cytoplasmic shuttling of class IIa histone deacetylases (HDAC4, -5, -7, and -9) is a synaptic activity-and nuclear calciumdependent mechanism important for epigenetic regulation of signal-regulated gene expression in hippocampal neurons. HDAC4 in particular has been linked to the regulation of genes important for both synaptic structure and plasticity. Here, using a constitutively nuclear-localized, dominant-active variant of HDAC4 (HDAC4 3SA), we demonstrate that HDAC4 accumulation in the nucleus severely reduces both the length and complexity of dendrites of cultured mature hippocampal neurons, but does not affect the number of dendritic spines. This phenomenon appeared to be specific to HDAC4, as increasing the expression of HDAC3 or HDAC11, belonging to class I and class IV HDACs, respectively, did not alter dendritic architecture. We also show that HDAC4 3SA decreases the expression of Vascular Endothelial Growth Factor D (VEGFD), a key protein required for the maintenance of dendritic arbors. The expression of other members of the VEGF family and of their receptors was not affected by the nuclear accumulation of HDAC4. VEGFD overexpression or administration of recombinant VEGFD, but not of VEGFC, the closest VEGFD homologue, rescued the impaired dendritic architecture caused by the nuclear-localized HDAC4 variant. These results identify HDAC4 as an epigenetic regulator of neuronal morphology that controls dendritic arborization via the expression of VEGFD.

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Soluble CD163 Changes Indicate Monocyte Association With Cognitive Deficits in Parkinson's Disease

et al. 2020

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A BS TRACT: Background: Parkinson's disease (PD) is a neurodegenerative disorder with a significant immune component, as demonstrated by changes in immune biomarkers in patients' biofluids. However, which specific cells are responsible for those changes is unclear because most immune biomarkers can be produced by various cell types. Objectives: The aim of this study was to explore monocyte involvement in PD. Methods: We investigated the monocyte-specific biomarker sCD163, the soluble form of the receptor CD163, in cerebrospinal fluid (CSF) and serum in two experiments, and compared it with other biomarkers and clinical data. Potential connections between CD163 and alpha-synuclein were studied in vitro. Results: CSF-sCD163 increased in late-stage PD and correlated with the PD biomarkers alpha-synuclein, Tau, and phosphorylated Tau, whereas it inversely correlated with the patients' cognitive scores, supporting monocyte involvement in neurodegeneration and cognition in PD. Serum-sCD163 increased only in female patients, suggesting a sex-distinctive monocyte response. CSF-sCD163 also correlated with molecules associated with adaptive and innate immune system activation and with immune cell recruitment to the brain. Serum-sCD163 correlated with proinflammatory cytokines and acute-phase proteins, suggesting a relation to chronic systemic inflammation. Our in vitro study showed that alpha-synuclein activates macrophages and induces shedding of sCD163, which in turn enhances alpha-synuclein uptake by myeloid cells, potentially participating in its clearance. Conclusions: Our data present sCD163 as a potential cognition-related biomarker in PD and suggest a role for monocytes in both peripheral and brain immune responses. This may be directly related to alpha-synuclein's proinflammatory capacity but could also have consequences for alpha-synuclein processing.

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Reciprocal Interaction of Dendrite Geometry and Nuclear Calcium–VEGFD Signaling Gates Memory Consolidation and Extinction

Cited by 18 publications

References 35 publications

Neuronal ensemble-specific DNA methylation strengthens engram stability

Neuronal ensemble-specific DNA methylation strengthens engram stability

Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D

Soluble CD163 Changes Indicate Monocyte Association With Cognitive Deficits in Parkinson's Disease

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