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Sex-dependent alterations in the physiology of entorhinal cortex neurons in old heterozygous 3xTg-AD mice
Frederic Calon
Centre de recherche du CHUL
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4203-0887
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Biology of Sex Differences.
While the higher prevalence of Alzheimer Disease (AD) is clear, studies suggest that biological sex may also influence its pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months. This brain region was selected because of its early association with AD symptoms. First, we found physiological differences between male and female non-transgenic mice, providing indirect evidence of axonal alterations in old females. Second, we observed a transgene-dependent elevation of the firing activity, post-burst after hyperpolarization (AHP) and spontaneous excitatory postsynaptic current (EPSC) activity, without any effect of sex. Third, the passive properties and the hyperpolarization-activated current (Ih) were altered by transgene expression only in female mice, whereas paired-pulse ratio (PPR) of evoked EPSC was changed only in males. Fourth, both sex and transgene expression were associated with changes in action potential properties. Consistent with previous work, higher levels of Aβ neuropathology were detected in 3xTg-AD females, whereas tau deposition was similar. In summary, our results support the idea that aging and AD neuropathology differentially alter the physiology of entorhinal cortex neurons in males and females.
Keywords
Alzheimer, aging, entorhinal cortex, 3xTg‐AD mice, electrophysiology
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This is a list of supplementary files associated with this preprint. Click to download.
- Supplementalfiguresforreviewers.pdf
- Fig.S1WBGAD65LyseBuffer.jpg
- Fig.S2WBGAD65andACTINLyseBuffer.jpg
- Fig.S3WBSAP102TBSbuffer.jpg
- Fig.S4WBActinTBSbuffer.jpg
- Fig.S5WBGAD65andActinPostStripTBSbuffer.jpg
- TableS120200909.jpg
Table S1: Statistical results of the pathological markers. The values of each group (t-value / pValue) are separated by a double vertical line (||). *p <0 .05, **p < 0.01 and ***p < 0.001
- TableS2.jpg
Table S2: Statistical results of electrophysiological experiments. The two-way ANOVA shows first effect of the genotype, followed by that of the sex. If variable interaction was detected, statistical comparisons between groups were performed depending on the variance equivalence between groups. An unpaired Student’s t test was performed to compare groups of equal variance whereas groups of data that failed Bartlett's tests of homogeneity of variances were analyzed by Welch’s t test. The values from Student’s / Welch’s t-tests are given accordingly to this order regarding the effect of: (1) transgene expression in females (NonTg females vs. 3xTg-AD females mice); (2) transgene expression in males (NonTg males vs. 3xTg-AD males); (3) sex in NonTg (NonTg males vs. NonTg females); and (4) sex in transgenic animals (3xTg-AD males vs. 3xTg-AD females). The values of each group (t-value / pValue) are separated by a double vertical line (||). Abbreviations: n, number of recorded cells; N, number of mice included in the statistic. *p < 0.05, **p < 0.01 and ***p < 0.001 (effect of transgene expression in animals of the same sex) *p < 0.05, **p < 0.01 and ***p < 0.001 (effect of sex in animals of the same genotype)
- TableS320200909.jpg
Table S3: Statistical results of molecular studies. The two-way ANOVA shows first effect of the genotype, followed by that of the sex. If variable interactions were detected, statistical comparisons between groups were performed depending on the variance equivalence between groups. An unpaired Student’s t test was performed to compare groups of equal variance whereas groups of data that failed tests for equal variance were analyzed by Welch’s t test. The values from Student’s / Welch’s t-tests are given accordingly to this order regarding the effect of: (1) transgene expression in females (NonTg females vs. 3xTg-AD females); (2) transgene expression in males (NonTg male vs. 3xTg-AD males); (3) sex in NonTg (NonTg males vs. NonTg females); and (4) sex in transgenic animals (3xTg-AD males vs. 3xTg-AD females). The values of each group (t-value / pValue) are separated by a double vertical line (||). The two-way ANOVA included three p-values, the effect of genotype (first), sex (second) and variable interaction (third). *p < 0.05 (effect of transgene expression in animals of the same sex) **p < 0.01 (effect of sex in animals of the same genotype)
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CURRENT STATUS: Published
Version 2
Posted 28 Sep, 2020
Published
On 16 Nov, 2020
No community comments so far
Editorial decision: Accept
On 14 Oct, 2020
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Received 13 Oct, 2020
Review #2 received
Received 13 Oct, 2020
Reviewers invited
Invitations sent on 25 Sep, 2020
Reviewer #1 agreed
On 25 Sep, 2020
Reviewer #2 agreed
On 25 Sep, 2020
Editor assigned
On 25 Sep, 2020
Submission checks complete
On 24 Sep, 2020
Editor invited
On 24 Sep, 2020
No comments provided
Editorial decision: Major Revision
On 05 Aug, 2020
Review #1 received
Received 05 Aug, 2020
Editor assigned
On 20 Jul, 2020
Reviewers invited
Invitations sent on 20 Jul, 2020
Reviewer #1 agreed
On 20 Jul, 2020
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On 19 Jul, 2020
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On 19 Jul, 2020
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On 17 Jul, 2020
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This preprint is under consideration at Biology of Sex Differences. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Sex-dependent alterations in the physiology of entorhinal cortex neurons in old heterozygous 3xTg-AD mice
Frederic Calon
Centre de recherche du CHUL
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4203-0887
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 28 Sep, 2020
Published
On 16 Nov, 2020
No community comments so far
Editorial decision: Accept
On 14 Oct, 2020
Review #1 received
Received 13 Oct, 2020
Review #2 received
Received 13 Oct, 2020
Reviewers invited
Invitations sent on 25 Sep, 2020
Reviewer #1 agreed
On 25 Sep, 2020
Reviewer #2 agreed
On 25 Sep, 2020
Editor assigned
On 25 Sep, 2020
Submission checks complete
On 24 Sep, 2020
Editor invited
On 24 Sep, 2020
No comments provided
Editorial decision: Major Revision
On 05 Aug, 2020
Review #1 received
Received 05 Aug, 2020
Editor assigned
On 20 Jul, 2020
Reviewers invited
Invitations sent on 20 Jul, 2020
Reviewer #1 agreed
On 20 Jul, 2020
Submission checks complete
On 19 Jul, 2020
Editor invited
On 19 Jul, 2020
First submitted
On 17 Jul, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Physiology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Biology of Sex Differences.
While the higher prevalence of Alzheimer Disease (AD) is clear, studies suggest that biological sex may also influence its pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months. This brain region was selected because of its early association with AD symptoms. First, we found physiological differences between male and female non-transgenic mice, providing indirect evidence of axonal alterations in old females. Second, we observed a transgene-dependent elevation of the firing activity, post-burst after hyperpolarization (AHP) and spontaneous excitatory postsynaptic current (EPSC) activity, without any effect of sex. Third, the passive properties and the hyperpolarization-activated current (Ih) were altered by transgene expression only in female mice, whereas paired-pulse ratio (PPR) of evoked EPSC was changed only in males. Fourth, both sex and transgene expression were associated with changes in action potential properties. Consistent with previous work, higher levels of Aβ neuropathology were detected in 3xTg-AD females, whereas tau deposition was similar. In summary, our results support the idea that aging and AD neuropathology differentially alter the physiology of entorhinal cortex neurons in males and females.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11