Brain cells adjust memory by weakening their connections. This study uncovered an unexpected signal inside cells that triggers this weakening, offering new clues to how learning and forgetting work.

Our memories are not fixed. The brain constantly reshapes them by strengthening or weakening the connections between nerve cells. Here, the word “shape” refers to how experiences are stored, adjusted, or even forgotten as neurons fine-tune their communication. A recent study by Shinji Matsuda and colleagues has revealed an unexpected signal inside brain cells that plays a key role in this adjustment process, shedding light on the delicate balance between learning and unlearning.

The researchers focused on a phenomenon known as long-term depression (LTD), in which neurons weaken their connections by reducing the number of AMPA-type glutamate receptors on their surface. In the hippocampus, this mechanism is thought to be important for erasing old memories and making room for new ones. In cultured hippocampal neurons, the team found that blocking a molecule called Toll-like receptor 9 (TLR9) prevented the usual removal of AMPA receptors after stimulation.
Reintroducing TLR9 restored the effect, showing that this receptor is essential for LTD.

The surprising part of the story lies in what activates TLR9. Rather than detecting invading microbes, as in the immune system, TLR9 in neurons responds to fragments of mitochondrial DNA released when mitochondria undergo stress and degradation. The researchers observed that stimulation of neurons led to mitophagy—the recycling of damaged mitochondria—and the release of mitochondrial DNA into the cytoplasm. This DNA bound to TLR9, triggering a chain of events that ultimately caused AMPA receptors to be internalized. When mitochondrial DNA replication or mitophagy was inhibited, the pathway was blocked, highlighting the central role of this “self-DNA” signal.

Further experiments showed that TLR9 activation leads to the engagement of caspase-3, an enzyme most often linked to cell death. In this case, however, caspase-3 acted in a controlled, non-lethal way to regulate receptor trafficking. This sequence—mitochondrial DNA release, TLR9 activation, and caspase-3 signaling—forms a newly described pathway by which brain cells weaken their connections during LTD.

This discovery challenges the conventional view of innate immune receptors as purely defensive tools and reveals a previously unknown role in everyday brain function. It also suggests new ways of thinking about how cellular stress influences memory.
Mitochondrial dysfunction is common in aging and in neurological disorders such as Alzheimer’s disease. The release of mitochondrial DNA and its detection by TLR9 may therefore provide a link between energy metabolism, immune signaling, and cognitive decline.

Reflecting on the broader significance of the findings, the authors note: “Our study shows that memory is not shaped by neurotransmitters alone. Signals from within the cell, such as mitochondrial DNA, can directly influence how neurons strengthen or weaken their connections. This gives us a new perspective on how learning and forgetting are regulated at the molecular level.”

Looking ahead, many questions remain. How does TLR9 communicate with caspase-3 in detail? Does this pathway operate during actual learning tasks in animals, not just in cultured cells? Could over-activation of this system contribute to disease, and might targeted therapies help preserve synapses in conditions of cognitive decline?

By uncovering a hidden role for TLR9 in brain cell communication, Atarashi and colleagues have identified a new molecular link between the cell’s inner machinery and the brain’s ability to adapt. Their findings not only deepen our understanding of the biology of memory but also open the door to potential strategies for protecting the brain against degeneration.