Entorhinal Cortex: Use it or lose it

Blocking the activity of neurons in a region of the brain involved in memory leads to cell death, which could help explain the spatiotemporal disorientation observed in Alzheimer’s disease.
  1. Ohad Rechnitz
  2. Dori Derdikman  Is a corresponding author
  1. Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Israel
  2. Bnai Zion Medical Center, Israel

Alzheimer’s disease is a neurodegenerative disorder that affects approximately 55 million people globally (Gauthier et al., 2021). One serious symptom of the disease is a tendency to become disorientated both in space and in time. Researchers attribute this, in part, to impairments in the medial temporal lobe of the brain, which includes the hippocampus and the entorhinal cortex. These two regions are involved in the formation and retrieval of memories; in particular, they are important for making spatial memories for navigation, including memories of place, time, head direction and environmental borders (see for example review by Knierim, 2015).

To encode new memories and retrieve past ones, neurons in the network formed by the entorhinal cortex and the hippocampus have to maintain their plasticity – that is, their ability to form new connections between cells and remove ones which are rendered obsolete throughout life. In mouse models of Alzheimer’s disease, however, the role of hippocampal and entorhinal cells in learning and memory is impaired (Rechnitz et al., 2021; Ying et al., 2022). As these regions are highly interconnected, early-stage corruption in the entorhinal region is further amplified downstream in the hippocampus. This leads to a vicious cycle that may impact behavior and cause spatial and temporal disorientation.

The specific mechanisms leading to a deterioration of the brain’s neural networks in Alzheimer’s disease are unclear. Similarly, it is unknown how this leads to memory loss. However, the impairment of neural networks within the entorhinal cortex often appears early in the progression of the disease (Stranahan and Mattson, 2010). Now, in eLife, Joanna Jankowsky and colleagues at Baylor College – including Rong Zhao, Stacy Grunke and Caleb Wood as joint first authors – report on how a neuronal population in layer II of the entorhinal cortex contributes to this impairment (Zhao et al., 2022). Their experiments show that blocking the activity of these neurons ultimately leads to increased cell death in this population.

Zhao et al. used a mouse model thought to undergo the same disruption to cell activity observed in Alzheimer’s disease. However, in this model, the impairment is not induced by the amyloid-beta plaques or neurofibrillary tangles characteristic of the disease. This is interesting because, even though it had previously been established that neurons die during Alzheimer’s disease, this was usually attributed to a vicious cycle of increased amyloid release driven by increased synchronization between cells causing hyperactivity (Busche and Konnerth, 2015; Zott et al., 2019). Instead, Zhao et al. show that, in their mouse model, cell deterioration and death in the entorhinal cortex are driven by silencing of specific neuronal activity.

Zhao et al. also demonstrate that, in their mouse model, a competitive process between active and inactive cells in the entorhinal cortex precedes neurodegeneration. This type of competition is similar to what is seen in infantile neuronal plasticity during development, when neural circuits are refined by selecting neurons and neural pathways depending on their levels of activity. Following this refinement process, which was previously thought to end soon after birth, some neurons degenerate while others persist. The extension of infantile neuronal plasticity in entorhinal cortex cells into adulthood may act as a double-edged sword: on the one hand, the plasticity allows these cells to form and modulate memories throughout life; on the other hand, the cells are more vulnerable to malfunction and death through competition.

Sensory information from multiple modalities (i.e. tactile, olfactory, auditory etc.) converges into layers II and III of the entorhinal cortex, which form the major input sources for two regions in the hippocampus, called the dentate gyrus and CA3. These areas of the brain are part of a pathway that ultimately terminates in another hippocampal region known as CA1 (Witter et al., 2000). It is therefore suggested that the cell impairment observed in the entorhinal cortex by Zhao et al. resembles an isolated deficit that can occur in Alzheimer’s disease. This impairment potentially forms an early seed to the later deterioration of neural networks and brain regions downstream, mainly in the hippocampus (Figure 1; Cacucci et al., 2008; Rechnitz et al., 2021; Roy et al., 2016). This may lead to the memory deficits and disorientation observed in Alzheimer’s patients.

The deterioration of neural networks following impairment of the entorhinal cortex may drive disorientation in Alzheimer’s disease.

(A) In healthy mice, the tri-synaptic pathway begins in the entorhinal cortex (MEC, pink) and terminates in the CA1 region (grey) of the hippocampus. A prominent population of stellate cells (dark blue) can be found in layer 2 (L2, pink) of the entorhinal cortex. First, signals travel from layer 2 of the entorhinal cortex through the perforant path (dark blue arrow) to the dentate gyrus (DG, light blue) and the CA3 (red). Signals then travel from the dentate gyrus to the CA3 through the mossy fibers (light blue arrow). From the CA3, signals are transmitted through axons known as Schaffer collaterals (red arrows) to the CA1. This pathway is known to be essential for the formation of spatial memory and navigation. The inset shows how a healthy mouse, in which this pathway is working correctly, can navigate a maze. (B) In mice models of Alzheimer’s disease, the results of Zhao et al. suggest that the stellate cells in the entorhinal cortex degenerate and corrupt the information transmitted through the tri-synaptic pathway (dashed arrows), leading to the disruption of the neural network downstream, neuronal loss and ultimately disorientation. The inset shows how an Alzheimer’s disease model mouse is unable to navigate a maze. MEC: medial entorhinal cortex; Sub: subiculum.

Figure credit: Dafna Antes.

The findings of Zhao et al. hold promise for potential new treatment strategies targeting the cell population in layer II of the entorhinal cortex early on in the Alzheimer's disease. These interventions have the potential to slow down the cascade of events leading to the onset of the condition.


Article and author information

Author details

  1. Ohad Rechnitz

    Ohad Rechnitz is in the Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, and the Bnai Zion Medical Center, Haifa, Israel

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4760-4667
  2. Dori Derdikman

    Dori Derdikman is in the Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3677-6321

Publication history

  1. Version of Record published: January 24, 2023 (version 1)


© 2023, Rechnitz and Derdikman

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 1,525
    Page views
  • 111
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ohad Rechnitz
  2. Dori Derdikman
Entorhinal Cortex: Use it or lose it
eLife 12:e85437.

Further reading

    1. Neuroscience
    E Nicholas Petersen, Mahmud Arif Pavel ... Scott B Hansen
    Research Article

    Rapid conversion of force into a biological signal enables living cells to respond to mechanical forces in their environment. The force is believed to initially affect the plasma membrane and then alter the behavior of membrane proteins. Phospholipase D2 (PLD2) is a mechanosensitive enzyme that is regulated by a structured membrane-lipid site comprised of cholesterol and saturated ganglioside (GM1). Here we show stretch activation of TWIK-related K+ channel (TREK-1) is mechanically evoked by PLD2 and spatial patterning involving ordered GM1 and 4,5-bisphosphate (PIP2) clusters in mammalian cells. First, mechanical force deforms the ordered lipids, which disrupts the interaction of PLD2 with the GM1 lipids and allows a complex of TREK-1 and PLD2 to associate with PIP2 clusters. The association with PIP2 activates the enzyme, which produces the second messenger phosphatidic acid (PA) that gates the channel. Co-expression of catalytically inactive PLD2 inhibits TREK-1 stretch currents in a biological membrane. Cellular uptake of cholesterol inhibits TREK-1 currents in culture and depletion of cholesterol from astrocytes releases TREK-1 from GM1 lipids in mouse brain. Depletion of the PLD2 ortholog in flies results in hypersensitivity to mechanical force. We conclude PLD2 mechanosensitivity combines with TREK-1 ion permeability to elicit a mechanically evoked response.

    1. Developmental Biology
    2. Neuroscience
    Athina Keramidioti, Sandra Schneid ... Charles N David
    Research Article

    The Hydra nervous system is the paradigm of a ‘simple nerve net’. Nerve cells in Hydra, as in many cnidarian polyps, are organized in a nerve net extending throughout the body column. This nerve net is required for control of spontaneous behavior: elimination of nerve cells leads to polyps that do not move and are incapable of capturing and ingesting prey (Campbell, 1976). We have re-examined the structure of the Hydra nerve net by immunostaining fixed polyps with a novel antibody that stains all nerve cells in Hydra. Confocal imaging shows that there are two distinct nerve nets, one in the ectoderm and one in the endoderm, with the unexpected absence of nerve cells in the endoderm of the tentacles. The nerve nets in the ectoderm and endoderm do not contact each other. High-resolution TEM (transmission electron microscopy) and serial block face SEM (scanning electron microscopy) show that the nerve nets consist of bundles of parallel overlapping neurites. Results from transgenic lines show that neurite bundles include different neural circuits and hence that neurites in bundles require circuit-specific recognition. Nerve cell-specific innexins indicate that gap junctions can provide this specificity. The occurrence of bundles of neurites supports a model for continuous growth and differentiation of the nerve net by lateral addition of new nerve cells to the existing net. This model was confirmed by tracking newly differentiated nerve cells.