Cell Rep: Early Alzheimer's disease may have neural circuit dysfunction during sleep

Homeostatic dysregulation of neural activity has been suggested as a possible mechanism promoting the pathology of Alzheimer's disease (AD)

It is well known that the deposition of amyloid (Aβ) occurs 10-20 years before the clinical manifestations of AD (cognitive function impairment, etc.

The team led by Professor Inna Slutsky conducted a series of studies on this problem and found that in AD model mice in a awake state before cognitive impairment symptoms appeared, the hippocampal neural circuit was not damaged, but during non-REM sleep (NREM) and under general anesthesia (decreased neuronal activity), dysfunction of neural circuit homeostasis in the hippocampus

The professor's team published an article entitled "Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models" in the journal Cell Reports in January 2022

1.

Hippocampal CA1 neuron activity is normal

The mice used in the experiment were 4-5 month old APP/PS1 gene mutant mice, which had obvious amyloid deposition (increased Aβ40, Aβ42 and the ratio of Aβ42 to Aβ40), but their cognitive function was not stable.

The experiment uses a wide-field head-mounted fluorescence micro-microscope to quickly and long-term track the dynamic changes of Ca2+ at the level of single neurons to display neuronal activity (Fig.

At the same time, the experiment also used long-term implanted quadrupole rods to directly record the firing activity of single neurons in mice

In addition, in the recording of extracellular field excitatory postsynaptic potentials, it was found that the synaptic transmission and short-term synaptic plasticity of hippocampal CA3-CA1 in APP/PS1 mice in the awake state were not significantly different from those in WT mice ( Figure JK)

Figure 1.

2.

MFR abnormalities in hippocampal CA1 neurons during

Normally, the activity of hippocampal CA1 neurons is downregulated during NREM (this is known as a local homeostatic mechanism)

Therefore, it can be concluded that a typical negative regulation of CA1 neurons in the hippocampus of APP/PS1 mice during NREM is obviously dysfunctional (Fig.

Figure 2.

3.

During NREM, the MFR of WT mice was lower than that in the awake state (Fig.

However, in APP/PS1 mice, no significant changes in MFR were found in either the awake or NREM state (Fig.
3B,E), probably because of the fraction of cells that were lower than the median MFR of neurons in the awake state.
Activity was elevated during NREM, whereas the activity of cells above the median was unchanged (Fig.
3F)
.

Considering that the overall slow-wave oscillation abnormality has previously occurred in AD patients and AD mouse models, in order to explore whether the above-mentioned changes in neuronal activity are due to the abnormal slow-wave oscillation, this experiment detected the EEG of mice and found that APP/PS1 The slow-wave EEG (Fig.
3G) and slow-wave local field potential (LFP) (Fig.
3H) of mice and WT mice were not significantly different
.
This indicates that the abnormal partial discharge rate of hippocampal CA1 neurons during NREM in APP/PS1 mice is earlier than the global slow wave oscillation abnormality
.

Figure 3.
The abnormal partial discharge rate of hippocampal CA1 neurons during NREM in APP/PS1 mice precedes the abnormal global slow wave oscillation

4.
Loss of APP/PS1 mice

Neuronal inhibitory function under general anesthesia

This experiment uses isoflurane (ISO) to induce anesthesia
.
It was found that under isoflurane exposure, WT mice exhibited marked suppression of the CA1 neuronal cell population (Fig.
4A,C), mainly due to a reduction in the number of active neuronal cells (Fig.
4C)
.

However, the CA1 neuronal cell population of APP/PS1 mice did not show significant inhibition (Fig.
4B,D), which ultimately resulted in no significant difference in overall neuronal activity under anesthesia and awake (Fig.
E)
.

Furthermore, APP/PS1 mice exhibited marked hypersynchrony, with greatly increased numbers of firing cells (Fig
.
After the experimenter used other anesthetics, the appeal results still appeared, indicating that the APP/PS1 mice lost the neuronal inhibitory function that should have occurred under general anesthesia
.

Figure 4.
APP/PS1 mice lose neuronal inhibitory function under general anesthesia

5.
Different fAD mouse models under anesthesia

hyperexcitability

This experiment used different transgenic AD mice to further confirm the above finding that under anesthesia, neuronal inhibition in APP/PS1 mice is dysfunctional
.
It was found that the above phenomenon still existed not only in APP/PS1 mice, but also in 5xFAD mice and APP-KI mice (Fig.
5A-C)
.
It is proved that this phenomenon is ubiquitous in AD model mice, not just a unique phenomenon in a single model AD mouse
.

Figure 5.
Different fAD mouse models exhibit hyperexcitability under anesthesia

6.
fAD mutations lead to downregulation of MFR homeostasis

This experiment uses in vitro hippocampal neuron multi-electrode arrays (MEAs) to examine MFR homeostasis mechanisms
.
It was found that the use of isoflurane resulted in a down-regulation of MFR levels in WT, fluctuating at a new decreasing set-point (Fig.
6A,C)
.
However, also in the isoflurane trial, the APP/PS1 mutation resulted in a decrease in MFR, but an immediate increase to a higher MFR level, corresponding to an increase in the set point (Fig.
6B,D)
.

This suggests that the APP/PS1 mutation resulted in marked hyperexcitability of hippocampal neurons compared with WT (Fig.
6E), but it did not impair the basic homeostatic regulatory response of the MFR (Fig.
FH)
.

Under normal circumstances, after the use of gamma-aminobutyric acid (GABA) receptor antagonists, the level of MFR will increase significantly, but its regulatory mechanism will slowly decrease the level of MFR, which is the case of WT hippocampal neurons ( Figure 6I)
.

However, APP/PS1 mutations lead to abnormal homeostatic regulation of this process, and in APP/PS1-mutated hippocampal neurons, MFR cannot be reduced to its original level, but is maintained at a high level continuously (Fig.
6J-K).

.

Figure 6.
In vitro experiments in hippocampal neurons found that fAD mutations lead to down-regulation of MFR homeostasis

7.
Inhibits mitochondrial mitochondrial dihydroorotate dehydrogenase

Can reduce the hyperexcitability of CA1 neurons under anesthesia

Mitochondrial DHODH enzymes can regulate MFR setpoints
.
Teriflunomide (TERI) is a DHODH enzyme inhibitor, and the experiment was carried out by injecting TERI into the ventricle of mice via vehicle (VEH)
.
It was found that epileptiform abnormal high-voltage electrical waves in CA1 neurons of APP/PS1 mice under anesthesia could be suppressed by TREI (Fig.
7C), and the firing rate was reduced (Fig.
7D-F)
.

Figure 7.
Teriflunomide (TERI) reduces hyperexcitability of CA1 neurons in APP/PS1 mice under anesthesia

in conclusion

In the early asymptomatic stage of AD, the CA1 neural network has been abnormal during anesthesia or non-REM sleep in the low excitability state, but there is no significant change in the awake state
.
This hyperexcitability can be alleviated by inhibitors of the DHODH enzyme that regulates MFR
.

references

Zarhin et al.
, 2022, Cell Reports 38, 110268 January 18, 2022.
https://doi.
org/10.
1016/j.
celrep.
2021.
110268.

Compilation author: KK (brainnews creative team)

Reviewer: Simon (Brainnews editorial department)

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