Significance: If the effects of a true PKMz conditional knockout result in memory impairments similar to the effects of ZIP, it will validate over a decade of work supporting PKMz as the molecular basis of memory maintenance. If the conditional knockout fails to block LTP maintenance, PKMz is not the major mechanism sustaining memory and other …show more content…
PKMz putatively facilitates LTP by maintaining trafficking of the Glu2R subunit of the AMPA receptor to the post-synaptic density, increasing the local synaptic potential and lowering threshold to depolarization at the membrane [28]. PKMz inhibitors can erase memories up to 3 months old, and GluA2 endocytosis inhibitors can block the loss of memory associated with ZIP [3]. Based on these observations, it has been proposed that PKMz and it’s downstream targets form a self-perpetuating, positive-feedback network through “synaptic auto-tagging” that can persist for months to maintain very long-term memories [3]. In order to preserve synaptic potentiation for such long periods, PKMz must be continuously produced and upregulated locally to constantly work against AMPAR …show more content…
If indeed PKMz does instigate an auto-regulatory feedback cycle to sustain LTP, what are the factors that determine it’s downregulation when the memories it maintains are no longer required? Proteolytic degradation of PKMz has been suggested as a possibility [21]. The neurotrophin BDNF has been shown to be required for PKMz-mediated LTP when protein synthesis is inhibited, revealing a possible role for BDNF in protecting active PKMz from degradation [7, 29]. Our unique experimental scheme will provide us with an ideal model to probe the translational regulation of PKMz at the synapse during both LTP and