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@ARTICLE{Jovasevic:268840,
author = {Jovasevic, Vladimir and Wood, Elizabeth M and Cicvaric, Ana
and Zhang, Hui and Petrovic, Zorica and Carboncino, Anna and
Parker, Kendra K and Bassett, Thomas E and Moltesen, Maria
and Yamawaki, Naoki and Login, Hande and Kalucka, Joanna and
Sananbenesi, Farahnaz and Zhang, Xusheng and Fischer, Andre
and Radulovic, Jelena},
title = {{F}ormation of memory assemblies through the {DNA}-sensing
{TLR}9 pathway.},
journal = {Nature},
volume = {628},
number = {8006},
issn = {0028-0836},
address = {London [u.a.]},
publisher = {Nature Publ. Group},
reportid = {DZNE-2024-00344},
pages = {145 - 153},
year = {2024},
abstract = {As hippocampal neurons respond to diverse types of
information1, a subset assembles into microcircuits
representing a memory2. Those neurons typically undergo
energy-intensive molecular adaptations, occasionally
resulting in transient DNA damage3-5. Here we found discrete
clusters of excitatory hippocampal CA1 neurons with
persistent double-stranded DNA (dsDNA) breaks, nuclear
envelope ruptures and perinuclear release of histone and
dsDNA fragments hours after learning. Following these early
events, some neurons acquired an inflammatory phenotype
involving activation of TLR9 signalling and accumulation of
centrosomal DNA damage repair complexes6. Neuron-specific
knockdown of Tlr9 impaired memory while blunting contextual
fear conditioning-induced changes of gene expression in
specific clusters of excitatory CA1 neurons. Notably, TLR9
had an essential role in centrosome function, including DNA
damage repair, ciliogenesis and build-up of perineuronal
nets. We demonstrate a novel cascade of learning-induced
molecular events in discrete neuronal clusters undergoing
dsDNA damage and TLR9-mediated repair, resulting in their
recruitment to memory circuits. With compromised TLR9
function, this fundamental memory mechanism becomes a
gateway to genomic instability and cognitive impairments
implicated in accelerated senescence, psychiatric disorders
and neurodegenerative disorders. Maintaining the integrity
of TLR9 inflammatory signalling thus emerges as a promising
preventive strategy for neurocognitive deficits.},
keywords = {Animals / Female / Male / Mice / Aging: genetics / Aging:
pathology / CA1 Region, Hippocampal: physiology /
Centrosome: metabolism / Cognitive Dysfunction: genetics /
Conditioning, Classical / DNA Breaks, Double-Stranded / DNA
Repair / Extracellular Matrix: metabolism / Fear / Genomic
Instability: genetics / Histones: metabolism / Inflammation:
genetics / Inflammation: immunology / Inflammation:
metabolism / Inflammation: pathology / Memory: physiology /
Mental Disorders: genetics / Neurodegenerative Diseases:
genetics / Neuroinflammatory Diseases: genetics / Neurons:
metabolism / Neurons: pathology / Nuclear Envelope:
pathology / Toll-Like Receptor 9: deficiency / Toll-Like
Receptor 9: genetics / Toll-Like Receptor 9: immunology /
Toll-Like Receptor 9: metabolism / Histones (NLM Chemicals)
/ Tlr9 protein, mouse (NLM Chemicals) / Toll-Like Receptor 9
(NLM Chemicals)},
cin = {AG Sananbenesi / AG Fischer},
ddc = {500},
cid = {I:(DE-2719)1410004 / I:(DE-2719)1410002},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38538785},
pmc = {pmc:PMC10990941},
doi = {10.1038/s41586-024-07220-7},
url = {https://pub.dzne.de/record/268840},
}