In APP Knock-In Mice, Spatial Mapping Circuitry Crumbles

People with Alzheimer’s get lost in once-familiar places, often quite early in their disease. A study published July 13 in Neuron helps explain why. Researchers led by Kei Igarashi at the University of California, Irvine, reported that in APP knock-in mice, grid cells in the entorhinal cortex start to degenerate just as Aβ plaques are emerging. Grid cells help with navigation, firing in distinct patterns as animals move around in their environment. But as these mice age, their grid cells start to lose connectivity with place cells in the hippocampus. This disconnection renders the hippocampus unable to recreate spatial maps—and the mice unable to distinguish between different environments. The findings suggest that the road to spatial memory loss starts in the entorhinal cortex, rather than the hippocampus.

  • In mice, firing patterns of grid and place cells adapt to the animal’s environment.
  • In APP knock-ins, this “remapping” fails, and spatial memory is lost.
  • Grid cells in the entorhinal cortex falter first, then hippocampal place cells.

“Spatially tuned” neurons—the grid and place cells—change their firing patterns in response to spatial location and environment (Fyhn et al., 2004; Cacucci et al., 2008; Doeller et al., 2010). Indeed, John O’Keefe, May-Britt Moser, and Edvard Moser shared the 2014 Nobel Prize for this discovery.

Neural circuitry between grid and place cells facilitates “remapping,” which is when distinct firing patterns are replicated in a specific environment. Remapping forms the basis of spatial memory (Fyhn et al., 2007; Kyle et al., 2015). Essentially, the mouse thinks, “I’ve been here before.”

Dysfunction of spatially tuned neurons has been reported in transgenic mouse models of amyloidosis and tauopathy (May 2008 news; Jan 2017 news). 

To investigate what happens to the spatial mapping circuitry in a model of amyloidosis that does not rely on overexpression, first author Heechul Jun and colleagues analyzed APP-KI mice, which express copies of human APP carrying three pathogenic AD mutations under control of the endogenous mouse APP promoter (Apr 2014 webinar). The mice develop Aβ deposition around 4 months of age, and spatial memory deficits emerge at 6 months. Indeed, the researchers found that while 12-month-old wild-type mice were able to distinguish a cage where they had received a foot shock from one in which they had not, 1-year-old APP-KI mice could not—they froze up in fear when placed into either.

The researchers started by recording the firing patterns of CA1 neurons, including place cells, in the hippocampus as mice foraged freely in an open field. They found that while place cells' firing patterns changed as the mice moved through space, the proportion of spatially tuned neurons in 7- to 13-month-old APP-KI mice was lower than in wild-type animals. More profound deficits emerged when mice were placed into two different contexts that they had previously explored. In APP-KI mice, the place-cell firing patterns evoked by the two locations overlapped, while in wild-type mice they were distinct. The finding hinted that the mice were having trouble holding maps of their environment in their memory.

Spatial Circuit. Neurons (red) in the medial entorhinal cortex send axons that form synapses with CA1 neurons in the hippocampus through the temporoammonic pathway. This circuitry is disrupted in APP-KI mice. [Courtesy of Jun et al., Neuron, 2020.]

Did this remapping deficit occur autonomously, or due to dysfunction of connected cells in the entorhinal cortex? Based on synchronization of gamma oscillations, the researchers determined that the circuitry between the medial entorhinal cortex and CA1 was disrupted, suggesting that hippocampal place cells were not receiving coordinated spatial inputs from the entorhinal cortex.

The researchers next focused their attention on grid cells in the medial entorhinal cortex, monitoring their firing patterns as the mice roamed. In contrast to the subtle loss of spatial tuning in hippocampal place cells, grid-cell firing pattern in APP-KI mice had little spatial relevance, firing randomly regardless of mouse location. While in wild-type mice about 20 percent of MEC neurons were bona fide grid cells, in APP-KI animals only 2 percent were.

More detailed electrophysiology experiments confirmed the deterioration of this circuit. Jun found that fast gamma oscillations emanating from the medial entorhinal cortex coordinated poorly with CA1 activity in the hippocampus.

All told, the finding indicated that neuronal problems underlying poor spatial navigation in these mice start in the entorhinal cortex. To probe this idea, the researchers examined 3- to 5-month-old APP-KI mice, whose spatial memory was still intact. They found that spatial tuning of grid cells in the medial entorhinal cortex was impaired, while CA1 remapping in the hippocampus was still viable. This suggests Aβ deposition first degrades the function of medial entorhinal cortex grid cells, and that this ultimately bungles remapping in connected place cells in the hippocampus, Igarashi told Alzforum.

Could similar circuits fail in people with AD? The authors caution that these mice carry three APP mutations, whereas people with AD have at most one, if that. Still, the findings mesh with a functional MRI study in cognitively normal people at risk for AD. It reported impaired grid-cell function in ApoE4 carriers who still had intact spatial memory (Oct 2015 news). These researchers also observed heightened activity in the hippocampi of ApoE4 carriers, and speculated that it could represent compensation for the faltering inputs from grid cells.

Igarashi said that because grid-cell dysfunction precedes remapping deficits and spatial memory loss, it could potentially serve as a functional biomarker for AD. While his study only looked at a model of amyloidosis, he thinks tau pathology, which starts in the entorhinal cortex early in disease, may also disrupt the spatial circuit.—Jessica Shugart

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References

News Citations

  1. Place Cells: New Way to Probe Spatial Memory in AD Mice
  2. Led Astray: Pathology Tied to “Grid Cell” Malfunction in Tauopathy Model
  3. Young ApoE4 Carriers Wander Off the ‘Grid’ — Early Predictor of Alzheimer’s?

Research Models Citations

  1. APP NL-G-F Knock-in

Webinar Citations

  1. Good-Bye Overexpression, Hello APP Knock-in. A Better Model?

Paper Citations

  1. Fyhn M, Molden S, Witter MP, Moser EI, Moser MB. Spatial representation in the entorhinal cortex. Science. 2004 Aug 27;305(5688):1258-64. PubMed.
  2. Cacucci F, Yi M, Wills TJ, Chapman P, O'Keefe J. Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7863-8. PubMed.
  3. Doeller CF, Barry C, Burgess N. Evidence for grid cells in a human memory network. Nature. 2010 Feb 4;463(7281):657-61. Epub 2010 Jan 20 PubMed.
  4. Fyhn M, Hafting T, Treves A, Moser MB, Moser EI. Hippocampal remapping and grid realignment in entorhinal cortex. Nature. 2007 Mar 8;446(7132):190-4. PubMed.
  5. Kyle CT, Stokes JD, Lieberman JS, Hassan AS, Ekstrom AD. Successful retrieval of competing spatial environments in humans involves hippocampal pattern separation mechanisms. Elife. 2015 Nov 27;4 PubMed.

External Citations

  1. 2014 Nobel Prize

Further Reading

No Available Further Reading

Primary Papers

  1. Jun H, Bramian A, Soma S, Saito T, Saido TC, Igarashi KM. Disrupted Place Cell Remapping and Impaired Grid Cells in a Knockin Model of Alzheimer's Disease. Neuron. 2020 Sep 23;107(6):1095-1112.e6. Epub 2020 Jul 21 PubMed.

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