The electrophysiological findings in this interesting paper appear solid. However, the suggestion that the place cell abnormalities are due to plaques appears premature to me. It is based on an incomplete set of data from mice at one time point, i.e., 16 months. Future studies should test a second and maybe third time point, for example, at 10 months or at 22 months, because in Tg2576 mice the behavioral impairment, and presumably the electrophysiological abnormalities in place cells, fail to change at rates that are commensurate with changes in plaque deposition. The conclusion that the place cell abnormalities are due to plaques can be drawn only if the correlations hold, when data from two widely separated time points are combined and analyzed together.

View all comments by Karen Hsiao Ashe

This article represents a clear, logically sound experiment in which the function of hippocampal place cells was monitored relative to spatial memory performance in an AD animal model. The authors’ rationale in investigating the relationship among place cells, amyloid, and impaired spatial function is justifiable and worthy. Another notable discussion point lies in the finding that behavioral deteriorations correlated significantly with all amyloid concentrations, while amyloid levels did not, in turn, correlate well with place cell functional quality. I agree with the interpretation of this as being indicative of the importance of the recruitment of the neocortex in the T-maze task. This, too, as addressed, would likely be an advantageous avenue of further study.

The results of this experiment provide another tool that may perhaps be helpful in the study of the pathology and the correlated behavioral deficits associated with AD. It would be interesting also to take this approach further and inspect the morphology of the individual place cells as well as their location in...  Read more

This article represents a clear, logically sound experiment in which the function of hippocampal place cells was monitored relative to spatial memory performance in an AD animal model. The authors’ rationale in investigating the relationship among place cells, amyloid, and impaired spatial function is justifiable and worthy. Another notable discussion point lies in the finding that behavioral deteriorations correlated significantly with all amyloid concentrations, while amyloid levels did not, in turn, correlate well with place cell functional quality. I agree with the interpretation of this as being indicative of the importance of the recruitment of the neocortex in the T-maze task. This, too, as addressed, would likely be an advantageous avenue of further study.

The results of this experiment provide another tool that may perhaps be helpful in the study of the pathology and the correlated behavioral deficits associated with AD. It would be interesting also to take this approach further and inspect the morphology of the individual place cells as well as their location in reference to nearby plaques. Also, it’s not clear that the authors checked to make sure the electrodes were actually implanted in place cells. I am surprised that the old wild-type mice did not do significantly poorer than the young groups.

View all comments by Hongxin Dong
View all comments by Nicole Hicklin

This article on hippocampal place cell firing and memory deficits and plaque burden provides a crucial piece of the amyloid-β puzzle: the relationship between neuropathology on the one hand and neuronal function on the other. While cognitive deficits have been well documented in APP mouse models, this is the first time that a direct neural correlate of such behavioral deficits has been shown. The central finding is the reduction of spatial information carried by the activity of hippocampal place cells in Tg2576 mice at ages at which significant plaque aggregation has occurred. This was directly observed by measuring changes in place field size and spatial information.

The correlation of the place cell activity deficits with percentage of plaque coverage in both hippocampal and cortical neurons is especially interesting. It strongly suggests that this particular deficit arises from the amount of aggregated amyloid-β, providing evidence for a specific effect of plaques on neuronal activity underlying behavior. The evidence is further bolstered by the finding that mean firing...  Read more

This article on hippocampal place cell firing and memory deficits and plaque burden provides a crucial piece of the amyloid-β puzzle: the relationship between neuropathology on the one hand and neuronal function on the other. While cognitive deficits have been well documented in APP mouse models, this is the first time that a direct neural correlate of such behavioral deficits has been shown. The central finding is the reduction of spatial information carried by the activity of hippocampal place cells in Tg2576 mice at ages at which significant plaque aggregation has occurred. This was directly observed by measuring changes in place field size and spatial information.

The correlation of the place cell activity deficits with percentage of plaque coverage in both hippocampal and cortical neurons is especially interesting. It strongly suggests that this particular deficit arises from the amount of aggregated amyloid-β, providing evidence for a specific effect of plaques on neuronal activity underlying behavior. The evidence is further bolstered by the finding that mean firing rate is not affected in these neurons, suggesting that the electrical properties of the neurons are not the cause of the change in functional neuronal properties. It is also interesting that the deficits in place cell firing are highly variable. This would be expected if the deficits are a result of distortion of the connectivity of the neuronal network, since the spatial distribution of plaques is also highly variable.

Although the findings of the current paper do not directly address the mechanism of the information deficit in the place cells, an in vivo intracellular recording study in similarly aged Tg2576 mice has shown similar losses of specific evoked neuronal response reliability in neocortical neurons without affecting spontaneous activity. Those results suggest that temporal disruption of synaptic activity (caused by the spatial distortion of the neuropil by plaques) results in reduction of the neurons’ ability to integrate the necessary afferent information (Stern et al., 2004).

The current paper shows behaviorally relevant loss of information-processing capability by individual neurons in brain areas with significant plaque aggregation during behavior—and correlated with performance deficit. The information deficit is in a (if not the) major functional role of these neurons, i.e., that of spatial localization and mapping. To my knowledge, this is the first study directly correlating AD neuropathology with changes in neuronal activity directly related to behavior—and correlated with behavioral deficit.

One further comment is warranted: these findings in no way detract from the numerous studies implicating the soluble, oligomeric forms of amyloid-β on neuronal activity; they simply provide evidence that the aggregated forms of amyloid-β play a separate, specific role in the disease process, and that role (in addition to that played by soluble amyloid-β) must be addressed in any therapeutic approach to the disease.

View all comments by Edward A. Stern