kinase A, which "fixes" the memory of the map. 



But how do stimuli lead to the release of the 

 neurotransmitters along the "right" neural path- 

 ways, marking the stimuli for special attention? In 

 implicit memory storage, exemplified by Aplysia's 

 increased sensitization through conditioning, the 

 attentional signal is called up involuntarily — re- 

 flexively — from the bottom up. The sensory neu- 

 rons, activated by a shock, act directly on the cells 

 that release serotonin. In the mouse's spatial mem- 

 ory, however, the attentional signal is called up in a 

 fundamentally different way. Dopamine appears to 

 be recruited from the top down. The cerebral cor- 



lllusions of size and distance may arise when the brain interprets space on the 

 basis of simple visual cues and learned expectations. If additional cues are 

 taken into account, however, the illusion is quickly replaced by a more robust 

 interpretation. The illusion is part of a temporary exhibit in the Deutches 

 Museum in Munich, Germany. 



tex activates the cells in the midbrain that release 

 dopamine, and dopamine modulates activity in the 

 hippocampus. Nevertheless, in learning to attend, 

 both from the top down and from the bottom up, 

 the underlying molecular mechanisms are similar. 



In 2004 Kausik Si, a postdoctoral fellow in my 

 laboratory, discovered that Aplysia carries a novel 

 form of a protein known as CPEB. The novel pro- 

 tein, ApCPEB, is present at all the synapses of the 

 sensory neurons of the gill- withdrawal reflex, where 

 it is activated by serotonin and is required for the 

 growth of new synaptic terminals [see illustration on 

 preceding two pages}. Si discovered that one end of 

 ApCPEB has all the characteristics of a prion. 



Prions are probably the weirdest proteins known 

 to modern biology. They cause several neuro- 

 degenerative diseases, such as mad cow disease in 

 cattle and Creutzfeldt-Jakob disease in people. 



What is unique about prions is that they can fold 

 into two distinct shapes that function in highly dif- 

 ferent ways. One shape is dominant, the other re- 

 cessive. The genes that encode prions give rise to 

 the recessive form. But the recessive form can con- 

 vert into the dominant form either by chance or as 

 a result of being exposed to the dominant form. 

 For example, the recessive prions in an animal can 

 take on the dominant form if the animal eats food 

 that contains the dominant form. 



Most proteins are subject to constant turnover, 

 degraded and destroyed in a few hours. But domi- 

 nant prions are self-perpetuating, because they can 

 trigger newly minted recessive prions to switch to 

 the dominant form as well, causing a chain reac- 

 tion. Thus their influence is tenacious. 



Soon after Si discovered the prionlike properties 

 of ApCPEB, we postulated that in Aplysia's sensory 

 neurons, serotonin might control the conversion of 

 ApCPEB from its inactive, nonpropagating, reces- 

 sive form to its active, propagating, dominant form. 

 In other words, the modulatory transmitter re- 

 quired for converting short-term to long-term 

 memory acts by creating dominant ApCPEB pro- 

 tein. And that protein apparently maintains newly 

 grown synaptic connections over long periods, per- 

 petuating memory storage. 



If confirmed, the discovery would be the first case 

 in which a physiological signal — serotonin — may be 

 critical in converting one prion form to another. It 

 would be also the first example of a self-propagating 

 prion form that serves a useful physiological func- 

 tion. In all other cases previously studied, the domi- 

 nant form either causes disease and death by killing 

 nerve cells or, more rarely, is inactive. 



After that finding in Aplysia, Martin Theis, a 

 postdoctoral fellow in my laboratory, and I began 

 testing the idea that, in much the same way, mouse 

 dopamine controls the conversion of another pri- 

 onlike protein known as CPEB-3 in the mouse 

 hippocampus. That raises the intriguing possibil- 

 ity — so far only that — that spatial maps may be- 

 come fixed when an animal's attention triggers the 

 release of dopamine in the hippocampus. That 

 dopamine might then initiate a self-perpetuating 

 state maintained by the dominant form of CPEB-3. 



If that idea proves correct, it would open up a new 

 biochemical approach to the stabilization of long- 

 term memory. Eventually, then, new drugs might 

 one day exploit those effects to treat Alzheimer's dis- 

 ease and other disorders of memory. □ 



This article was adapted from In Search of Memory: The Emergence 

 of a New Science of Mind, by Eric R. Kahdel, which is being pub- 

 lished this month by WW Norton & Company, Inc. Copyright© 2006 

 by Eric R. Kandel 



38 



natural history March 2006 



