The way individuals’ memories of experiences are created and represented across neuron assemblies in hippocampal and cortical circuits has remained a complex and intriguing field of study. One of the most known mechanisms of memory formation is the stimulus-induced long-term potentiation of synaptic connectivity, an energy-demanding process requiring extensive biochemical and morphological adjustments at all levels of neuronal function.
A recent scientific expose in Nature journal, led by Vladimir Jovasevic et al., explores a new mechanism of memory formation that ranges across stimulus-dependent and pre-existing mechanisms in neurons commitment to memory-specific assemblies.
Researchers discovered that as hippocampal neurons respond to various information types, a subset assembles into microcircuits that represent a memory. Occasionally, these neurons undergo energy-consuming molecular adaptations resulting in transient DNA damage.
In the aftermath of learning experiences, distinct clusters of excitatory hippocampal CA1 neurons were found to experience persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures, and a subsequent release of histone and dsDNA fragments. Following these early events, some neurons acquire an inflammatory phenotype triggered by a mechanism called TLR9 signaling.
Activated mainly due to intracellular DNA damage, TLR9 triggers a cascade of adaptive and protective responses to safeguard the cell from the harmful effects caused by premature DNA replication and genotoxic stress.
Herein, we profile TLR9’s integral contribution to memory circuits.
- TLR9 belongs to a class of notable proteins – toll-like receptors (TLRs), crucial for the innate immune system.
- Normally expressed on cells that act as immune sentinels like macrophages and dendritic cells, TLR proteins identify structurally conserved molecules from pathogens.
- Once detected, TLRs prompt active immune cell responses that culminate in the activation of immune responses.
- In humans, the TLR9 gene encodes the TLR9 protein whose essential functions include pathogen recognition and the activation of innate immunity.
- TLR9 resides intracellularly and alerts the immune system of viral and bacterial infections by binding to CpG motifs-rich DNA.
- Unchecked DNA degradation and cell damage can cause modulated TLR9 expression, contributing to autoimmune diseases.
The study concludes, TLR9 plays an indispensable role in centrosome function, including DNA damage repair, ciliogenesis, and the formation of perineuronal nets. If TLR9 function is compromised, it leads to genomic instability and cognitive impairments associated with accelerated aging, psychiatric, and neurodegenerative disorders.
These groundbreaking findings highlight the potential of maintaining TLR9 inflammatory signaling integrity as a promising approach to prevent neurocognitive deficits and potentially inform treatment options for diverse neurologically connected dysfunctions.
Reference 1: Jovasevic, Vladimir, et al. “Formation of Memory Assemblies through the DNA-sensing TLR9 Pathway.” Nature, 2024
Reference 2: Johnson, Gifford B., et al. “Cutting Edge: The TLR9 Is Important for the Recognition of Bacteria.” Journal of Immunology, 2002
Reference 3: Krieg, Arthur M. “CpG Motifs in Bacterial DNA and their Immune Effects.” Annual Review of Immunology, 2002