(4) prions

In 1999 [lab partner] Kausik Si found that a novel form of CPEB in Aplysia was present only in the nervous system, at all the synapses of a neuron, activated by serotonin, and required at the activated synapses to maintina…new terminals…As Kausik looked carefully at the amino acid sequence of the novel CPEB, he noticed something very peculiar. One end of the protein had all the characteristics of a prion. Prions are probably the weirdest proteins known to modern biology…The genes that encode prions give rise to the recessive form, but the recessive form can be converted to the dominant form…The dominant form is self-perpetuating; it causes the recessive conformation to change its shape as well…I remember it was a beautiful New York afternoon in the spring of 2001…when Kausik walked into my office and asked, “what would you say if I told you that the CPEB has prion-like properties?” Clearly, a self-perpetuating molecule could remain at a synapse indefinitely, regulating the local protein synthesis needed to maintain newly grown synaptic terminals. In my late-night thoughts about long-term memory, I had once briefly entertained the idea that prions might somehow be involved in long-term memory storage.

In 1992, we found that by knocking out a particular gene encoding a protein that is important for LTP, we could compromise synaptic strengthening in the Schaffer collateral pathway. Morever, the genetic defect was correlated with a defect in the mouse’s spatial memory.
I examined slices of the hippocampus taken from genetically modified mice and found that in each of the three major pathways of the hippocampus, LTP has two phases similar to those of LTP in Aplysia. A single train of electrical stimuli produces a transient, early phase of LTP that lasts only one to three hours and does not require the synthesis of new protein. NMDA receptors in the postsynaptic cel are activated, leading to the flow of calcium ions inot the postsynaptic cell. Here calcium acts as asecond messenger; it triggers LTP by enhancing the existing AMPA receptors’ response to glutamate and by stimulating the insertion of new AMPA receptors into the membrane of the postsynaptic cell…Repeated trains of electrical stimuli produce a late phase of long-term potentiation that lasts for more than a day…by modulatory interneurons. In mice those neurons release dopamine…Like serotonin in Aplysia, dopamine prompts a receptor in the hippocampus to activate an enzyme that increases the amount of cyclic AMP…which recruits protein kinase A and other protein kinases, which leads to the activation of CREB and the turning on of effector genes…I discovered that the mammalian brain requires several gene regulators in addition to CREB.

We found that although neither protein kinase A nor protein synthesis is needed for the initial formation of a spatial map, they both are essential for the map to become “fixed” over the long term, so that the mouse recalls the same map every time it enters the same space…When we blocked protein kinase A or inhibited protein synthesis, we interfered not only with the long-term stability of the spatial map but also with the ability to retain long-term spatial memories…We found that blocking the action of dopamine in the hippocampus blocked the stabilization of the spatial map in an animal that was paying attention. Conversely, activating dopamine receptors in the hippocampus stabilized the spatial map of an animal that was not paying attention…In implicit memory storage, the attentional signal is recruited involuntarily (reflexively), from the bottom up: the sensory neurons of the tail, activated by a shock, act directly on the cells that release serotonin. In spatial memory, dopamine appears to be recruited voluntarily, from the top down: the cerebral cortex activates the cells that release dopamine, and dopamine modulates activity in the hippocampus…The hippocampus of the mouse contains at least one prion-like protein…Dopamine modulates the amount of the prion-like CPEB protein (CPEB-3) in the mouse hippocampus. This discovery raised the intriguing possibility—so far only that—that spatial maps may become fixed when an animal’s attention triggers the release of dopamine in the hippocampus and that dopamine initiates a self-perpetuating state also mediated by CPEB.

We explored the Schaffer collateral pathway in the hippocampus of older mice with age-related memory deficits and found that the late phase of long-term potentiation, which we and others had found to be strongly correlated with long-term explicit memory, was defective…We had found earlier that the late phase of long-term potentiaion is mediated by cyclic AMP and protein kinase A and that this signaling pathway is activated by dopamine…We found that drugs which activate these dopamine receptors, and thereby overcome the deficit in the late phase of long-term potentiaion. They also reverse the hippocampus-dependent memory deficit…The drug Rolipram inbhits the enxyme that breaks down cyclic AMP,increasing signaling. In old mice, I found, Rolipram significantly improves learning that involves the hippocampus…Rolipram even increased long-term potentiaion and hippocampus-dependent memory in young animals…Exposing the mouse hippocampus to the most toxic component of B-amyloid plaques, known as the AB peptide…impairs LTP before any neurons die or plaques form. The peptide decrease the activity of cyclic AMP and protein kinase A.