30 August 2002. The Memory-Fading Phosphatase
Isabelle Mansuy, David Genoux, and colleagues at the Swiss Federal Institute of Technology in Zurich and at the University of Washington in Seattle report that protein phosphatase 1 (PP1) actively suppresses memory formation, both in the short term and over time.
Molecular studies have established that the removal of phosphate groups (by phosphatases) and the opposing addition of these subunits by kinases play a role in processes like long-term potentiation that are believed to underlie the storage of memories (e.g. Blitzer et al 1998). Mansuy's group set out to study the behavioral effects of manipulating one of these enzymes. They generated transgenic mice in which expression of an endogenous PP1 inhibitor, called inhibitor 1, can be turned on by feeding the mice an antibiotic. These mice develop normally, and the researchers can selectively inhibit PP1 during learning experiments.
Their initial experiments confirmed classic findings by the German researcher Ebbinghaus from the 19th century showing that shorter training sessions spaced well apart (distributed training) result in stronger memories than do fewer, longer sessions (massed training). Mansuy and colleagues also found that PP1 was more active during the massed training. One possible functional explanation for this effect is that the brain can't store too much memory at once, and PP1 is giving the brain a chance to consolidate memories.
The researchers then demonstrated that when they turned on inhibitor 1, PP1 was suppressed and memories formed during massed training sessions were equally strong as those gained during distributed training. Thus, the authors concluded, PP1 is an active suppressor of memory formation.
In the second part of their behavioral experiments, the researchers investigated whether PP1 was also a "forgetting" molecule in the sense of suppressing memories that have already been formed. They found that when tested for memories that had been encoded weeks earlier, control mice had gradually lost their memories. PP1-suppressed mice, on the other hand, retained strong memories for up to 6 weeks later, whether the initial training had been done in a massed or distributed manner.
As for the molecular underpinnings of this "enhanced" learning, the authors report that it correlated with increased phosphorylation of several proteins: cyclic AMP-dependent response element binding (CREB) protein, Ca[2+]/calmodulin-dependent protein kinaseII(CaMKII), and the GluR1 subunit of the AMPA receptor. It also correlated with CREB-dependent gene expression that only occurs with distributed, but not massed, training in control mice.
Finally, Mansuy et al. asked whether PP1 might be a viable therapeutic target for older adults with age-related cognitive decline. When they tested 15- to 18-month old mice, they found that the mutant mice with inhibited PP1 were significantly better than control mice at remembering their training.
The ApoE4 Allele Handicaps Non-Demented Elderly
There is strong prior evidence that carrying the 4 allele of the apolipoprotein E gene is a risk factor for Alzheimer's disease, and yesterday’s Nature contains evidence that E4 carriers who reach old age without developing dementia nonetheless suffer greater cognitive decline than those who do not carry this allele.
Ian Deary, John Starr, Martha Whiteman and colleagues at the University of Edinburgh and other institutions in Scotland tested 466 nondemented 80-year-old people on the same IQ test that they had taken 69 years earlier as 11-year-olds. While there had been no significant difference at age 11 between those who did or didn't carry the E4 allele, the 80-year-olds with the E4 allele scored significantly worse than their compatriots.
The authors acknowledge that this performance difference could point to early, undetected Alzheimer's disease amongst the E4 group. However, their statistical analysis based on comparisons with previous studies among E4 carriers showed that a much higher percentage of E4 carriers had score reductions than the expected percentage of AD sufferers would be. They suggest that future studies might identify other ways in which the ApoE4 variant could affect cognition, for example via atherosclerosis or other disorders.
"Identifying a factor that influences non-pathological, lifetime cognitive changes has large public-health implications because in the absence of a sharp risk threshold, most adverse events-and most of the personal and economic burdens that these bring-occur to old people who are within the 'normal' part of the distribution," the authors write.—Hakon Heimer.
Reference:Genoux D, Haditsch U, Knobloch M, Michalon A, Storm D, Mansuy IM. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature. 29 Aug 2002;418:970-75. Abstract
Silva AJ, Josselyn SA. The molecules of forgetfulness. Nature. 29 Aug 2002;418:929-30. Abstract
Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ. Cognitive change and the APOE epsilon4 allele. Nature. 29 Aug 2002;418:932. Abstract