<IMG SRC="" CLASS="FR-FIC FR-FIL FR-DIB FR-DRAGGABLE"><IMG SRC="" CLASS="FR-FIC FR-FIL FR-DIB FR-DRAGGABLE">ROLE OF PIEZO1 MECHANOTRANSDUCTION IN HIPPOCAMPAL NEUROGENESIS

Hippocampal neurogenesis in the dentate gyrus is regulated by biochemical and mechanical cues. Recent evidence suggests that the dentate gyrus exhibits a gradient of tissue stiffness from the soft neurogenic niche to the stiffer outer layers of granule cells. Neural stem cells (NSCs) are mechanosensitive and can sense changes in tissue and extracellular matrix stiffness during proliferation, differentiation, and maturation. This project aimed to investigate the role of the mechanosensitive ion channel, Piezo1, in regulating hippocampal neurogenesis.

Organotypic hippocampal slice cultures from wild-type CD1 mice were treated with GsMTx-4, an inhibitor of Piezo1, or Yoda1, a selective positive allosteric modulator of Piezo1 channel opening. Neurogenic and proliferative activity were assessed using the immunofluorescent markers Ki67 or EdU co-labelled with NeuN to quantify newly generated neurons. Quantitative image analysis demonstrated a significant 29% decrease in EdU-positive cell numbers in GsMTx-4–treated slices (p = 0.0015). Conversely, increasing doses of Yoda1 (i.e. 1, 3, and 10 µM) resulted in a dose-dependent increase in the number of EdU-positive cells (p = 0.0127), suggesting that Piezo1-mediated calcium (Ca2+) influx positively regulates neurogenesis. Proteomic analysis of hippocampal synaptosomes revealed enrichment of proteins associated with lipid modification and calcium-dependent phospholipid binding, indicating that Piezo1 activation alters synaptic membrane dynamics.

These findings highlight the pivotal role of mechanotransduction in regulating the neurogenic niche of the dentate gyrus, indicating Piezo1 as a compelling therapeutic target. Understanding these molecular mechanisms of neurogenesis may contribute to the development of precision-based interventions for cognitive deficits associated with neurodevelopmental disorders.