ENGINEERING HIPPOCAMPAL SYNAPTIC CONNECTIONS IN AGED MICE

With increasing life expectancy, cognitive decline has emerged as a major societal concern. In the hippocampus, the efficiency of signal transmission from CA3 to CA1 declines with age, contributing to impaired cognitive function. We hypothesized that selectively eliminating a subset of axon terminals could strengthen remaining synapses and mitigate age-related synaptic weakening. To test this hypothesis, we employed a previously validated Synthetic Trogocytosis (SynTrogo) system, in which GFP displayed on CA3 Schaffer collateral axon membranes is recognized by GFP nanobody–expressing astrocytes in the CA1 region, enabling selective binding and engulfment of presynaptic terminals.

In the aged hippocampus, SynTrogo induced artificial nibbling of presynaptic axons, leading to uptake of excitatory presynaptic components by astrocytes. Notably, aged mice also exhibited uptake of inhibitory postsynaptic elements, suggesting an age-dependent alteration of the synaptic molecular landscape. Following SynTrogo treatment, axon terminal density decreased, whereas postsynaptic structures underwent pronounced remodeling, accompanied by changes in synaptic transmission.

Patch-clamp recordings from CA1 pyramidal neurons revealed an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and a decrease in spontaneous inhibitory postsynaptic currents (sIPSCs). These findings indicate a functional shift in the balance of excitatory and inhibitory inputs at the circuit level in the aged hippocampus. Such synaptic remodeling improved memory retention and extinction learning, ultimately contributing to recovery of hippocampus-dependent cognitive function. Together, our results demonstrate that SynTrogo alleviates cognitive decline in aged mice through age-specific mechanisms distinct from those observed in young mice, involving structural reorganization and circuit-level modulation of excitatory/inhibitory balance.