Formation of memory assemblies through the DNA-sensing TLR9 pathway

Vladimir Jovasevic, Elizabeth M. Wood, Ana Cicvaric, Hui Zhang, Zorica Petrovic, Anna Carboncino, Kendra K. Parker, Thomas E. Bassett, Maria Moltesen, Naoki Yamawaki, Hande Login, Joanna Kalucka, Farahnaz Sananbenesi, Xusheng Zhang, Andre Fischer and Jelena Radulovic ()
Additional contact information
Vladimir Jovasevic: Northwestern University
Elizabeth M. Wood: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Ana Cicvaric: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Hui Zhang: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Zorica Petrovic: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Anna Carboncino: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Kendra K. Parker: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Thomas E. Bassett: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
Maria Moltesen: Aarhus University
Naoki Yamawaki: Aarhus University
Hande Login: Aarhus University
Joanna Kalucka: Aarhus University
Farahnaz Sananbenesi: University Medical Center
Xusheng Zhang: Albert Einstein College of Medicine
Andre Fischer: University Medical Center
Jelena Radulovic: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine

Nature, 2024, vol. 628, issue 8006, 145-153

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07220-7

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