Abstract
Long-Term Potentiation (LTP), a crucial form of synaptic plasticity essential for memory and learning, depends on protein synthesis and the upregulation of GluA1 at postsynaptic terminals. While extensive research has focused on the role of endosomal trafficking in GluA1 regulation, the contribution of endoplasmic reticulum (ER) trafficking pathways remains largely unexplored. A key opportunity to investigate this emerged from Ykt6, an evolutionarily conserved SNARE protein and a master regulator of vesicular fusion along ER-trafficking pathways. Here, we demonstrate that Ykt6 is highly expressed in the mammalian hippocampus, where it localizes to synaptic spines and regulates GluA1 surface expression in an LTP-dependent manner. Furthermore, we found that Ykt6 modulates synaptic vesicle pool dynamics as well as the amplitude and frequency of miniature excitatory postsynaptic currents. Ykt6 loss of function has been linked to α-synuclein pathology, a hallmark of Lewy Body Dementias (LBDs), where α-synuclein misfolding in the hippocampus disrupts LTP. Taken together, our findings establish Ykt6 as a critical SNARE protein in hippocampal function during LTP, with significant implications for neurodegenerative disorders such as LBDs.