Viral delivery of Pla2g2f to the dentate gyrus helped 16-month-old mice recognize a relocated object
Viral delivery of Pla2g2f to the dentate gyrus helped 16-month-old mice recognize a relocated object
A study published on October 15 in Nature Neuroscience examined how the aging brain responds to synapse loss. The researchers identified PLA2G2F, whose levels increased after this loss. They then disabled its gene, increased production of the protein, and compared the active enzyme with a catalytically inactive variant. In a separate human cell model, they traced signaling from neurons to microglia.
The dentate gyrus is a region of the hippocampus that helps distinguish similar memories, allowing an animal to recognize when a familiar object has moved to a different location. Connections between its neurons become sparser with age. The researchers looked for a signal that neurons produce in response to this loss.
In a previously established model, a temporary increase in KLF9, a protein that regulates gene expression, reduced the number of dendritic spines on adult granule neurons. These spines receive most incoming signals, so the model produced a measurable loss of synapses. The team then analyzed the cells’ RNA and found a 1,93-fold increase in Pla2g2f gene activity.
When the researchers disabled Pla2g2f in dentate gyrus neurons, the mice had fewer dendritic spines. Microglia, the brain’s immune cells, showed stronger signs of inflammation, while astrocytes, which support neurons, showed greater reactivity. In a memory test, mice with the gene disabled spent equal amounts of time exploring the stationary and relocated objects.
In a separate group of 16-month-old mice, the researchers delivered a viral vector carrying Pla2g2f into the dentate gyrus to increase neuronal production of PLA2G2F. Five weeks later, these mice spent more time exploring the relocated object; the behavioral experiment included nine mice per group. Separate measurements in groups of the same age showed fewer reactive astrocytes and less pronounced signs of inflammation in microglia.
PLA2G2F is a secreted phospholipase, an enzyme that breaks down membrane lipids and generates molecules used in signaling between cells. In 17-month-old mice, the active enzyme reduced lipid droplet accumulation and glial reactivity; the catalytically inactive variant had neither effect. This control shows that these effects require the enzyme’s catalytic activity. Microglia in the naked mole-rat accumulate far more lipid droplets than mouse microglia, yet remain in a non-inflammatory state. In this study, the researchers assessed lipid droplets alongside glial reactivity.
The researchers tested the same neuron-to-microglia signaling pathway in a human cell model. Medium collected from brain organoids, three-dimensional cell cultures, with elevated PLA2G2F reduced lipid droplets in microglia derived from reprogrammed human cells. These findings suggest that PLA2G2F may contribute to a mechanism that helps the aging mouse brain maintain memory.