04 Oct 2008

The molecular mechanisms behind the reorganization of synapses that leads to memory storage are the subject of a trio of studies published this week. In the lead story, Kimberly Maguschak and Kerry Ressler of Emory University in Atlanta, Georgia, implicate the adhesion receptor and signaling molecule β-catenin in the synaptic restructuring that underlies long-term memory in vivo. β-catenin is more often associated with development and cell survival pathways, but by both pharmacologic and genetic approaches in mice, the investigators find that its stabilization is essential for the conversion of new information into long-term memories in the amygdala. Published in the 28 September Nature Neuroscience, the new data are consistent with previous in-vitro studies showing a role for β-catenin in synapse remodeling. The links are also intriguing based on long-standing observations that β-catenin is associated in cells with presenilin proteins, a link whose functional consequence for synapses is still not clear.

A separate pair of papers in the October 1 Journal of Neuroscience add two additional players to the remodeling team. Michael Kessels, Britta Qualmann, and colleagues at the Friedrich Schiller University in Jena, Germany, reveal that the actin binding protein Abp1 serves as an essential bridge between the components of the postsynaptic density and the actin cytoskeleton, and helps to drive the reorganization of the cytoskeleton during synapse formation. Lastly, the calcium/calmodulin-dependent kinase, CaMKIV, is implicated in synaptic plasticity and age-related memory loss by a study from Satoshi Kida at the Tokyo University of Agriculture, Min Zhou of the University of Toronto in Ontario, Canada, and colleagues. Interestingly, overexpression of CaMKIV in a transgenic mouse prevented age-related memory loss in that study.

β-catenin has received much attention for its role as the cadherin counter-receptor in cell-cell adhesion and as a player in the Wnt signaling pathway in development and cancer, but there is also significant data linking the protein to synaptic activity and plasticity, at least in vitro (for review, see Salinas and Price, 2005). Maguschak and Ressler looked at the role of β-catenin in memory in vivo, using a fear conditioning paradigm. When mice are exposed to a tone and given a mild foot shock at the same time, they learn to associate the tone with the painful stimulus, and will later freeze in fear at the sound of the tone alone. Such fear memories reside in the amygdala, and the researchers found that β-catenin mRNA was increased there after the training. Levels of protein were not significantly changed, but its phosphorylation increased at Tyr654, a site that regulates affinity for cadherin. In addition, fear training enhanced inhibitory phosphorylation of the kinase GSK3β, thus preventing the kinase from destabilizing β-catenin. The results suggested that fear training stabilizes β-catenin and affects its cadherin-binding function.

To ask whether changes in β-catenin affect learning, the investigators treated mice with lithium, an inhibitor of GSK3β and thus a stabilizer of β-catenin, or made conditional knockouts to delete β-catenin in the amygdala. In either case, the results supported a crucial role for β-catenin in fear learning: stabilization of the protein enhanced the fear behavior, while deletion impaired it. The defect appeared to affect memory consolidation. Mice lacking β-catenin learned normally during conditioning, but did not remember the association in later trials. Deletion of β-catenin after training did not erode long-term memory, suggesting again that protein is required at the point of memory consolidation, but not for long-term maintenance.

The results point to a dynamic regulation of β-catenin function in the process of synaptic remodeling and memory formation. As the authors write, “These findings suggest that the affinity of β-catenin for cadherin initially weakens to allow for modifications of the synapse, and then strengthens to stabilize the synapse, which we hypothesize to be a molecular and cellular correlate of memory consolidation.”

“There is a pretty large literature showing that β-catenin plays some role in synaptogenesis, but our data is the first to show it in vivo, in the animal,” Ressler told ARF. He noted in particular the work of Erin Schuman of CalTech, who has shown that β-catenin is involved in synaptogenesis in hippocampal and cortical neurons (Murase et al., 2002) One question that will need to be settled is whether β-catenin’s effects stem from cell-cell adhesion, Wnt signaling, or both.

Does this pathway also operate in the hippocampus in vivo? Ressler told ARF that Maguschak is currently doing similar studies with conditional hippocampal knockouts. “The early returns suggest that knocking β-catenin out in the hippocampus also gives hippocampal deficits. We think that β-catenin is going to be a general molecular mechanism of synaptic plasticity, learning, and memory,” he said.

The reorganization of synapses that occurs when memories are laid down, and perhaps also when they are later lost in AD, is driven both by movements in synaptic proteins and by changes in cell shape driven by the actin cytoskeleton. The link between those two becomes a little clearer with the data from Kessels and Qualmann. First authors Akvile Haeckel and Rashmi Ahuja used in-vitro expression to dissect the function of different domains of the actin binding protein Abp1, which is localized in postsynaptic spines. In their study, increasing expression of Abp1 caused more mature, mushroom-shaped spines to appear, and boosted the number of synapses. Decreasing Abp1 expression with RNA interference had the opposite effect. The carboxy terminal end of the protein, they found, associates with the postsynaptic density components, while the amino terminal binds actin and participates in complexes that promote actin polymerization.

Lastly, could improving memory ever be as simple as boosting the activity of a kinase? Work from Zhou and Kida points in that direction, in mice. CaMKIV, like its better-known cousin CaMKII, is an upstream regulator of the transcription factor CREB. The induction of gene expression through the CREB pathway is well known to function in memory storage, and previous studies have implicated CaMKIV, too, in memory regulation. First author Hotaka Fukushima and colleagues made a transgenic mouse that overexpresses CaMKIV in the forebrain. When the investigators trained the animals in a contextual fear conditioning paradigm that coupled foot shock with environmental cues (in contrast to the sound stimulus used by Maguschak and Ressler), they found increased hippocampal CREB phosphorylation, as they expected. The transgenic mice had higher basal and stimulated levels of CREB modification, and performed better in several memory tests than wild-type mice. Consistent with this, the transgenic mice showed greater long-term potentiation in isolated hippocampal cells.

CaMKIV has been reported to be decreased in aging people (see ARF related news story), and the researchers confirmed this result in wild-type mice. They found that in aged mice, the extent of memory decline correlated with CaMKIV levels. The transgenic mice, who had shown higher memory function earlier in life, continued to outstrip the wild-type mice in old age. The results, taken together with previous work showing that boosting CREB can also ameliorate aging-related memory problems in rats, lead the authors to conclude that the CaMKIV-CREB signaling pathway “might therefore be a major target of drug development for the improvement of memory disorders including age-related memory deficits.”—Pat McCaffrey

Making Memories Stick Takes β-Catenin Adhesion Receptors, and More

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