Memory maintenance by PKMζ — an evolutionary perspective

Long-term memory is believed to be maintained by persistent modifications of synaptic transmission within the neural circuits that mediate behavior. Thus, long-term potentiation (LTP) is widely studied as a potential physiological basis for the persistent enhancement of synaptic strength that might sustain memory. Whereas the molecular mechanisms that initially induce LTP have been extensively characterized, the mechanisms that persistently maintain the potentiation have not. Recently, however, a candidate molecular mechanism linking the maintenance of LTP and the storage of long-term memory has been identified. The persistent activity of the autonomously active, atypical protein kinase C (aPKC) isoform, PKMζ, is both necessary and sufficient for maintaining LTP. Furthermore, blocking PKMζ activity by pharmacological or dominant negative inhibitors disrupts previously stored long-term memories in a variety of neural circuits, including spatial and trace memories in the hippocampus, aversive memories in the basolateral amygdala, appetitive memories in the nucleus accumbens, habit memory in the dorsal lateral striatum, and elementary associations, extinction, and skilled sensorimotor memories in the neocortex. During LTP and memory formation, PKMζ is synthesized de novo as a constitutively active kinase. This molecular mechanism for memory storage is evolutionarily conserved. PKMζ formation through new protein synthesis likely originated in early vertebrates ~500 million years ago during the Cambrian period. Other mechanisms for forming persistently active PKM from aPKC are found in invertebrates, and inhibiting this atypical PKM disrupts long-term memory in the invertebrate model systems Drosophila melanogaster and Aplysia californica. Conversely, overexpressing PKMζ enhances memory in flies and rodents. PKMζ persistently enhances synaptic strength by maintaining increased numbers of AMPA receptors at postsynaptic sites, a mechanism that might have evolved from the general function of aPKC in trafficking membrane proteins to the apical compartment of polarized cells. This mechanism of memory may have had adaptive advantages because it is both stable and reversible, as demonstrated by the downregulation of experience-dependent, long-term increases in PKMζ after extinction and reconsolidation blockade that attenuate learned behavior. Thus, PKMζ, the “working end” of LTP, is a component of an evolutionarily conserved molecular mechanism for the persistent, yet flexible storage of long-term memory.