CA3 HYPERACTIVITY DRIVES HIPPOCAMPAL CA1 NEURONAL DYSFUNCTION IN AGING

Recent studies show, in humans, an hyperactivation of the posterior hippocampus during navigation tasks. In aged rodents, electrophysiological studies report divergent activity profiles of CA1 pyramidal neurons. Some studies describe increased CA1 activity linked to glutamatergic transmission and/or Ca²⁺ dysregulation, whereas others report reduced CA1 firing, potentially driven by an increased post-burst afterhyperpolarization. To address this apparent paradox, we combined state-of-the-art approaches including patch-clamp electrophysiology, chemogenetics, pharmacology, and behavioral analyses in rodents. Whole-cell recordings from CA1 pyramidal neurons in 18-month-old male mice revealed a reduced paired-pulse ratio (PPR), consistent with increased presynaptic glutamate release, while intrinsic excitability remained unchanged. Furthermore, simultaneous assessment of excitatory and inhibitory postsynaptic currents revealed a disrupted excitatory/inhibitory (E/I) balance in aged neurons, shifted towards excitation. To test causality, we employed a chemogenetic viral strategy to selectively and chronically increase the activity of CA3 pyramidal neurons in young adult male mice (4 months). This manipulation was sufficient to induce aging-like hippocampal and behavioral phenotypes, including reduced PPR, disrupted E/I balance, and impaired spatial memory. Our findings suggest that CA1 dysfunction in aging is driven primarily by aberrant CA3 hyperactivity rather than by intrinsic CA1 alterations. These data contribute to understanding the synaptic mechanisms underlying hippocampal dysfunction in aging.
Funded by FCT (UI/BD/154567/2022), ANR-15-IDEX-01 and EU MSCA-SE-2021 Aquasynapse (#101086453).