(3) CREB

Longterm memory is not simply an extension of short-term memory: not only do the changes in synaptic strength last longer but, more amazingly, the actual number of synapses in the circuit changes…We could see for the first time that the number of synapses in the brain is not fixed—it changes with learning!

I had a hunch that long-term memory, which involves enduring changes in synaptic strength, could be tracked to changes in the genetic machinery of sensory neurons.

[Richard Scheller, a lab partner] succeeded in isolating the gene that controls egg laying [in Aplysia] and showed that it encodes a peptide hormone…He synthesized the peptide hormone, injected it into Aplysia, and watched as it set off the animal’s whole egg-layign ritual.

In short-term memory, synapses use cAMP and protein kinase A inside the cell to call for the release of more neurotransmitter. I hypothesized that in long-term memory this kinase moves from the synapse to the nucleus, where it somehow activates proteins that regulate gene expression…We now collaborated with Roger Tsien at UCSD and used a method developed by him that allowed us to visualize the location of the cAMP and protein kinase A in the neuron. We found that whereas a single pulse of serotonin increases cAMP and protein kinase A primarily at the synapse, repeated pulses of serotonin produce even higher concentrations of cAMP, causing protein kinase A to move into the nucleus, where it activates genes…We knew from recently published studies of non-neuronal cells that protein kinase A can activate a regulatory protein called CREB, which binds to a promoter…In 1990, we found that CREB is present in the sensory neurons of Aplysia and is indeed essential tot eh long-term strengthening of synaptic connections…In 1995 [a lab partner] found that there are in fact two forms of the CREB protein: one that activates gene expression (CREB-1) and one that suppresses gene expression (CREB-2). Repeated stimulation causes protein kinase A and MAP kinase to move to the nucleus, where protein kinase A activates CREB-1 and MAP kinase inactivates CREB-2…CREB’s opposing regulatory actions provide a threshold for memory storage, presumably to ensure that only important, life-serving experiences are learned…In 1993 Tim Tully discovered that CREB proteins are essential for long-term memory in Drosophila. As in Aplysia, CREB activators and repressors played critical roles. The CREB repressor blocked the conversion of short-term memory to long-term memory. Even more fascinating, mutant flies bred to produce more copies of the CREB activator had the equivalent of flashbulb memories.

In principle, a highly emotional state could bypass the normal restraints on long-term memory…This might account for socalled flashbulb memories, memories of emotionally charged events that are recalled in vivid detail—like my experience with Mitzi—as if a complete picture had been instantly and powerfully etched on the brain.

When we inhibited local protein synthesis at a synapse, new terminals grew, making use of the proteins sent to the synapse from the cell body. That new growth could not be sustained, however, and after one day it regressed…Two independent mechanisms are at work. One process initiates long-term synaptic facilitation by sending protein kinase A to the nucleus to activate CREB, thereby turning on the effector genes that encode the proteins needed for the growth of new synaptic connections. The other process perpetuates memory storage by maintaining the newly grown synaptic terminals, a mechanism that requires local protein synthesis.