Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer’s circuit dysfunction
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eLife assessment
This is a fundamental study that demonstrates that ongoing neuronal activity plays a key role in the vulnerability of specific neuronal cell types in layer 2 of the entorhinal cortex that communicates with the hippocampus. The authors provide compelling evidence that chronic silencing of inhibitory but not excitatory neurons in the entorhinal cortex leads to their degeneration. Reelin-positive interneurons were the most vulnerable to silencing. The authors propose that developmental mechanisms associated with activity-dependent programmed cell death could be aberrantly reactivated in the context of Alzheimer's disease.
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Abstract
Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Here, we show that entorhinal cortex layer 2 (EC2) neurons are unusually vulnerable to prolonged neuronal inactivity compared with neighboring regions of the temporal lobe, and that reelin + stellate cells connecting EC with the hippocampus are preferentially susceptible within the EC2 population. We demonstrate that neuronal death after silencing can be elicited through multiple independent means of activity inhibition, and that preventing synaptic release, either alone or in combination with electrical shunting, is sufficient to elicit silencing-induced degeneration. Finally, we discovered that degeneration following synaptic silencing is governed by competition between active and inactive cells, which is a circuit refinement process traditionally thought to end early in postnatal life. Our data suggests that the developmental window for wholesale circuit plasticity may extend into adulthood for specific brain regions. We speculate that this sustained potential for remodeling by entorhinal neurons may support lifelong memory but renders them vulnerable to prolonged activity changes in disease.
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eLife assessment
This is a fundamental study that demonstrates that ongoing neuronal activity plays a key role in the vulnerability of specific neuronal cell types in layer 2 of the entorhinal cortex that communicates with the hippocampus. The authors provide compelling evidence that chronic silencing of inhibitory but not excitatory neurons in the entorhinal cortex leads to their degeneration. Reelin-positive interneurons were the most vulnerable to silencing. The authors propose that developmental mechanisms associated with activity-dependent programmed cell death could be aberrantly reactivated in the context of Alzheimer's disease.
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Reviewer #1 (Public Review):
The authors serendipitously discovered that silencing Reln+ stellate neurons from medial entorhinal cortex layer II (mEC2) transiently by hyperpolarizing them causes them to degenerate. They replicate this result with two different tools to hyperpolarize these neurons, as well as with a tool to inhibit synaptic vesicle release at mECII axon terminals. They gain mechanistic insight into the degeneration process by performing a careful time course of axon morphological changes and caspase activation: somatic hyperpolarization causes axon retraction bulbs, while inhibition of glutamate release causes axon fragmentation. Crucially, they find that, unlike mEC2 neurons, neighboring Wfs1+ pyramidal cells or parasubicular cells do not degenerate when silenced in similar ways.
The vulnerability of mEC2 to inactivity …
Reviewer #1 (Public Review):
The authors serendipitously discovered that silencing Reln+ stellate neurons from medial entorhinal cortex layer II (mEC2) transiently by hyperpolarizing them causes them to degenerate. They replicate this result with two different tools to hyperpolarize these neurons, as well as with a tool to inhibit synaptic vesicle release at mECII axon terminals. They gain mechanistic insight into the degeneration process by performing a careful time course of axon morphological changes and caspase activation: somatic hyperpolarization causes axon retraction bulbs, while inhibition of glutamate release causes axon fragmentation. Crucially, they find that, unlike mEC2 neurons, neighboring Wfs1+ pyramidal cells or parasubicular cells do not degenerate when silenced in similar ways.
The vulnerability of mEC2 to inactivity is particularly compelling because the authors use three different tools to demonstrate it, two that hyperpolarize neurons (ivermectin-mediated activation of the modified glycine receptor alpha subunit, expressed transgenically; and Kir2.1 overexpression using AAV stereotaxic injection), and one that inhibits synaptic vesicle release at mEC2 terminals (Tetanus toxin overexpression using AAV stereotaxic injection). Each of these tools has its flaws but taken together the findings are very convincing. A few pieces of evidence that the various tools are achieving exactly what the authors say they are achieving are missing. But again, the convergence of the data between the three tools compensates for this to some extent.
I found the significance of the findings really fundamental and the writing of the paper absolutely remarkable - beautifully structured, crystal clear in its articulations and its implications. This paradigm has the potential to reveal crucial biology about plasticity in the adult, and about degeneration and vulnerability mechanisms. Vulnerability is such an important topic common to most neurodegenerative diseases, with absolutely no hints, until now, of what could render some cells more prone to degeneration, and immense potential for the discovery of central disease mechanisms. Even if degeneration relies here on the overexpression of an exogenous protein, it does not rely on the overexpression of a pathological protein directly associated with neurodegeneration, or on the invalidation of an essential protein. There is nothing trivial about the degeneration phenotype observed here, which makes the observations absolutely fascinating. What's more the authors show here evidence for the Grail of vulnerability: the side-by-side comparison of two similar/neighboring cell types treated in the same way, only one of which undergoing degeneration (Reln+ EC2 neurons Wfs1+ EC2 and parasubiculum neurons). The vulnerable cell type here also happens to be the very cell type that is most vulnerable to degeneration in Alzheimer's disease.
These findings are of major importance for a few different reasons:
- Neuronal excitability is clearly an early event occurring in the EC of incipient Alzheimer's disease. This study suggests that the silencing of certain cells by Alzheimer's lesions might contribute to their degeneration.
- A competition-based mechanism for the survival or degeneration of axons and neurons from EC2, is known to operate during development until the end of critical periods. This study suggests that EC2 neurons, which might be particular for their need to be plastic into adulthood, might use these mechanisms as well.
- Again, they establish a paradigm for the mechanistic study of comparative vulnerability between cell types that can be investigated further to understand the molecular underpinnings of degeneration. -
Reviewer #2 (Public Review):
One major enigma in neurodegeneration is why it tends to start many times in the entorhinal cortex. This paper tries to address this issue, by showing the vulnerability of reelin-positive entorhinal cells to inactivation, thus leading to the compelling idea that neurodegenerative processes are initiated by prolonged brain inactivity in specific brain regions. The paper is straightforward and performs a whole set of experiments to demonstrate the specificity of the effect on these cells, trying to partially decipher the underlying mechanisms which lead to the vulnerability of these specific cells.
The paper performs a series of tests on these cells. First, the chemogenetic silencing of layer 2 entorhinal neurons causes cell death and axonal degeneration. Second, this effect is specific to entorhinal neurons …
Reviewer #2 (Public Review):
One major enigma in neurodegeneration is why it tends to start many times in the entorhinal cortex. This paper tries to address this issue, by showing the vulnerability of reelin-positive entorhinal cells to inactivation, thus leading to the compelling idea that neurodegenerative processes are initiated by prolonged brain inactivity in specific brain regions. The paper is straightforward and performs a whole set of experiments to demonstrate the specificity of the effect on these cells, trying to partially decipher the underlying mechanisms which lead to the vulnerability of these specific cells.
The paper performs a series of tests on these cells. First, the chemogenetic silencing of layer 2 entorhinal neurons causes cell death and axonal degeneration. Second, this effect is specific to entorhinal neurons and spares other regions. Third, the effect seems to be mediated by synaptic silencing, in addition to general neuronal inactivity, and finally - the effect seems to be governed by neuronal competition and not by a general non-specific change in neuronal activity levels.
I think the paper is a great first step. In the future, more work will be needed in order to better understand the causes of this vulnerability and to connect this work to the cascade of neurodegeneration leading to the known phenomena associated with AD.
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