Abstract
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.
Highlights
Long-term memory is believed to be maintained by persistent modifications of synaptic transmission within the neural circuits that mediate behavior
In the 1980s and early 1990s, further studies in molluscan and insect model systems lead to the discovery of several signaling molecules that initiate long-term changes in synaptic transmission and behavior, including the cAMP-dependent protein kinase (PKA) [2,3] and the transcription factor, cAMP response element-binding protein (CREB) [4,5], which were shown to be crucial for memory formation in rodents and other animals [6]
Over a hundred signaling molecules downstream of the NMDA receptor were characterized [12]. Some, such as Ca2+/calmodulin-dependent protein kinase II (CaMKII), initiate a transient early-long-term potentiation (LTP) [13], whereas others, like mitogen-activated protein kinase (MAPK), participate in the regulation of new protein synthesis that is crucial for the transition from early- to more persistent late-LTP [14,15]
Summary
The persistent increased activity of PKMζ maintains LTP and perpetuates many, but not all, forms of long-term memory. The role of atypical PKM in maintaining long-term memory may have emerged as a specialized mechanism for persistently increasing postsynaptic AMPARs from the more general function of aPKC in membrane protein trafficking to the apical compartment of polarized cells. The origin of the mechanism of lateLTP by new synthesis of atypical PKM can be traced to early vertebrates in the Cambrian period. This synaptic information storage mechanism proved capable of recording experiences within neural circuits in a way that was both stable for months, yet reversible as new contingencies arise, and appears to have been useful for animal survival for hundreds of millions of years.
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