REGULATION OF STRUCTURAL AND FUNCTIONAL SYNAPTIC PLASTICITY BY MECHANOSENSITIVE PIEZO1 CHANNELS IN THE HIPPOCAMPUS

Aging process comes with an increased susceptibility to cognitive decline caused by alterations in brain connectivity and synaptic dysfunction within specific brain regions. One key alteration is the inflammation-driven accumulation in the extracellular matrix that coincides with increased tissue stiffness and the activation of mechanotransduction pathways. Mechanotransduction signaling can control specific gene expression and posttranslational modifications and may disrupt synaptic plasticity through mechanosensitive channel–mediated Ca²⁺ dysregulation. Therefore, this study aimed to investigate the expression and function of Piezo1 channels in the mouse brain. First, the expression of the main mechanosensitive channels was compared in the hippocampus of young (2-4 months) and aged (>30 months) C57BL6/J male mice. An age-associated increase was found in the expression of the Piezo1 and 2 channels, and some members of the TRP channel family. To isolate the contribution of Piezo1, we treated young hippocampal slices with Yoda1, a chemical activator of Piezo1, which impaired long-term potentiation in CA1 region. Furthermore, the structural plasticity changes induced by a chemical LTP protocol, such as increased mushroom spine density, were impaired by Yoda1 treatment. Additionally, by knocking down Piezo1 expression in aged mice, we observed a partial rescue of synaptic plasticity and cognitive function. These findings suggest that upregulation of signaling via mechanosensitive ion channels occurs in aged mice and that inhibiting this mechanism could potentially rescue age-related cognitive decline. Moreover, we discuss relevance of these data for experiments using transcranial magnetic and ultrasonic stimulation of the brain as these may activate signaling through Piezo1 channels.