TY  - JOUR
AU  - Jovasevic, Vladimir
AU  - Wood, Elizabeth M
AU  - Cicvaric, Ana
AU  - Zhang, Hui
AU  - Petrovic, Zorica
AU  - Carboncino, Anna
AU  - Parker, Kendra K
AU  - Bassett, Thomas E
AU  - Moltesen, Maria
AU  - Yamawaki, Naoki
AU  - Login, Hande
AU  - Kalucka, Joanna
AU  - Sananbenesi, Farahnaz
AU  - Zhang, Xusheng
AU  - Fischer, Andre
AU  - Radulovic, Jelena
TI  - Formation of memory assemblies through the DNA-sensing TLR9 pathway.
JO  - Nature
VL  - 628
IS  - 8006
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DZNE-2024-00344
SP  - 145 - 153
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Female
KW  - Male
KW  - Mice
KW  - Aging: genetics
KW  - Aging: pathology
KW  - CA1 Region, Hippocampal: physiology
KW  - Centrosome: metabolism
KW  - Cognitive Dysfunction: genetics
KW  - Conditioning, Classical
KW  - DNA Breaks, Double-Stranded
KW  - DNA Repair
KW  - Extracellular Matrix: metabolism
KW  - Fear
KW  - Genomic Instability: genetics
KW  - Histones: metabolism
KW  - Inflammation: genetics
KW  - Inflammation: immunology
KW  - Inflammation: metabolism
KW  - Inflammation: pathology
KW  - Memory: physiology
KW  - Mental Disorders: genetics
KW  - Neurodegenerative Diseases: genetics
KW  - Neuroinflammatory Diseases: genetics
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Nuclear Envelope: pathology
KW  - Toll-Like Receptor 9: deficiency
KW  - Toll-Like Receptor 9: genetics
KW  - Toll-Like Receptor 9: immunology
KW  - Toll-Like Receptor 9: metabolism
KW  - Histones (NLM Chemicals)
KW  - Tlr9 protein, mouse (NLM Chemicals)
KW  - Toll-Like Receptor 9 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38538785
C2  - pmc:PMC10990941
DO  - DOI:10.1038/s41586-024-07220-7
UR  - https://pub.dzne.de/record/268840
ER  -