"The current concept is that when you understand something, you enhance relationships between your minds known as synapses," describes Rich Huganir, Ph.D., a lecturer and home of the Johns Hopkins University School of Medicine's Division of Neuroscience. "The query is, how exactly does this building up happen?"
A analysis group at SUNY Downstate, led by Todd Sacktor, Ph.D., has recommended that key to the procedure is an compound they discovered, known as PKMζ (pronounced PKM-zeta). In 2006, Sacktor's group made surf when it designed a compound that seemed to prevent the activity of PKMζ -- and only PKMζ. When the compound, known as ZIP, was given to rats, it removed current long-term reminiscences. The compound captured the interest of correspondents and blog writers, who mused on the public and moral significances of storage erasure.
But for scientists, ZIP was interesting mainly as a way for studying PKMζ. "Since 2006, many documents have been released on PKMζ and ZIP, but no one realized what PKMζ was performing on," says Lenora Volk, Ph.D., a participant of Huganir's group. "We believed that studying the enzyme's focus on could tell us a lot about how reminiscences are saved and managed."
For the current study, Volk and fellow team member Julia Bachman made mice that lacked working PKMζ, so-called genetic "knockouts." The goal was to compare the synapses of the modified mice with those of normal mice, and find clues about how the enzyme works. But, says Volk, "what we got was not at all what we expected. We thought the strengthening capacity of the synapses would be impaired, but it wasn't." The brains of the mice without PKMζ were indistinguishable from those of other mice, she says. Additionally, the synapses of the PKMζ-less mice responded to the memory-erasing ZIP molecule just as the synapses of normal mice do.
The team then considered whether, in the absence of PKMζ, the mouse brains had honed a substitute synapse-building pathway, much in the way that a blind person learns to glean more information from her other senses. So the researchers made mice whose PKMζ genes functioned normally until they were given a drug that would suddenly shut the gene down. This allowed them to study PKMζ-less adult mice that had had no opportunity to develop a way around the loss of the gene. Still, the synapses of the so-called conditional knockout mice responded to stimuli just as synapses in normal mice did.
What this means, the researchers say, is that PKMζ is not the key long-term memory molecule previous studies had suggested, although it may have some role in memory. "We don't know what this ZIP peptide is really acting on," says Volk. "Finding out what its target is will be quite important, because then we can begin to understand at the molecular level how synapses strengthen and how memories form in response to stimuli." Other authors on the paper are Richard Johnson and Yilin Yu, both of the Johns Hopkins University School of Medicine.
