Neonatal LPS exposure reduces ATP8A2 level in the prefrontal cortex in mice via increasing IFN-γ level
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Abstract
Neonatal lipopolysaccharide (LPS) exposure can cause depressive-like behaviors in rodents involving elevated interferon (IFN)-γ. Studies have linked down-regulation of prefrontal cortex (PFC) ATPase phospholipid transporting 8A2(ATP8A2) expression to depressive-like behaviors. In non-neuronal cells, IFN-γ could reduce ATP8A2 expression. We therefore hypothesized that neonatal LPS exposure might induce PFC ATP8A2 down-regulation by increasing IFN-γ level. Here, C57BL6/J mice of both sexes received 3-dose-injections of LPS (50μg/kg bodyweight, i.p.) on postnatal day (PND)5, PND7 and PND9. LPS-treated mice showed a transiently decreased PFC ATP8A2 expression. Moreover, a negative correlation of PFC ATP8A2 expression was found with IFN-γ level. Using neutralizing mAb, IFN-γ was identified as the key mediator of LPS-induced PFC ATP8A2 decrease. Besides, neutralizing IFN-γ during neonatal LPS exposure attenuated the depressive-like behaviors in adulthood. In sum, neonatal LPS exposure reduced ATP8A2 level in PFC in mice via increasing IFN-γ level, maybe associated with mechanism underlying LPS-induced brain and behavior impairments.
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Reviewer #2:
The authors show that neonatal LPS (nLPS) treatment is associated with downregulated PFC levels of ATPase phospholipid tranporting8A2 (ATP8A2) that is associated with elevated IFN in serum and PFC and blocked by an IFN blocking antibody. Antibody treatment marginally antagonized effects of nLPS to cause depressive-like behavior, but was ineffective when females alone were examined.
This paper adds to a long list of publications reporting alterations in a number of diverse signaling molecules after nLPS treatment. Strengths are that it is generally well done, with appropriate attention to experimental design (eg litter effects) and statistical treatment. However, while the down regulation of ATP8A2 is indisputable, a major weakness is that there is no functional relationship revealed between this and any subsequent …
Reviewer #2:
The authors show that neonatal LPS (nLPS) treatment is associated with downregulated PFC levels of ATPase phospholipid tranporting8A2 (ATP8A2) that is associated with elevated IFN in serum and PFC and blocked by an IFN blocking antibody. Antibody treatment marginally antagonized effects of nLPS to cause depressive-like behavior, but was ineffective when females alone were examined.
This paper adds to a long list of publications reporting alterations in a number of diverse signaling molecules after nLPS treatment. Strengths are that it is generally well done, with appropriate attention to experimental design (eg litter effects) and statistical treatment. However, while the down regulation of ATP8A2 is indisputable, a major weakness is that there is no functional relationship revealed between this and any subsequent behavioral, anatomical or physiological alterations. While the possible role of IFN in causing the increased depressive-like behavior is of some interest, the data here are not convincing. Furthermore, while other work has reported extensively on sex-specific alterations in behavior after nLPS, the behavioral analysis here ( FST, TST) is rather limited.
There is little justification for reverting to the non-alpha corrected LSD test when the Tukey does not show significance.
The extensive literature on the effects of nLPS is only superficially reviewed.
The direct involvement of ATP8A2 in any behavioral or functional outcomes should be tested.
How does IFN cause down regulation of the ATP8A2?
Other behavioral alterations should be tested such as open field that are less stressful than FST or TST.
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Reviewer #1:
This report makes a logical connection between depressive-like behaviors induced in mice following LPS-injection to mimic bacterial infection and the down regulation of phospholipid transporting enzyme, ATP8A2, in the prefrontal cortex. The intermediary is IFN-gamma. The work is quite convincing that LPS down regulates ATP8A2 by upregulating IFN-gamma and that this has some limited effects on behavior. However, the impact of the findings is limited by several factors.
The use of FST and TST as measures of depression is increasingly falling out of favor as there is no face validity to humans. It is understood that these tests have been long in use and were in the past considered the best measures of "depressive-like" behaviors in mice but the field has moved on to much more relevant constructs such as social defeat, …
Reviewer #1:
This report makes a logical connection between depressive-like behaviors induced in mice following LPS-injection to mimic bacterial infection and the down regulation of phospholipid transporting enzyme, ATP8A2, in the prefrontal cortex. The intermediary is IFN-gamma. The work is quite convincing that LPS down regulates ATP8A2 by upregulating IFN-gamma and that this has some limited effects on behavior. However, the impact of the findings is limited by several factors.
The use of FST and TST as measures of depression is increasingly falling out of favor as there is no face validity to humans. It is understood that these tests have been long in use and were in the past considered the best measures of "depressive-like" behaviors in mice but the field has moved on to much more relevant constructs such as social defeat, anhedonia etc. As it stands the behavioral analysis here is limited and the effects are modest at best.
The use of LPS as a model to induce depression also has limitations. The injection paradigm used is likely to have caused massive inflammation, as evidenced by the increase in cytokines, but what this is modeling is unclear and how the impact would be specific to depression later in life is equally unclear. Indeed, the references the authors cite for the LPS regime they use offer completely different mechanisms and impacts of the inflammation. This is not to say the current findings aren't important, they are, but rather this pathway may be one among many that is invoked following massive inflammation during early development which then has many non-specific effects.
There is no functional connection between down regulation of ATP8A2 developmentally and adult neural activity. Clearly a membrane phospholipid transporting enzyme is important, but exactly how it is important here, meaning what enduring impacts there are on neuronal function, is unknown.
The experiments were designed to test the relationship between IFN-gamma and ATP8A2 but then conclude that the behavioral effects are mediated by this connection. There could be many other effects of IFN-gamma that are not considered here but would be nonetheless blocked by the neutralizing antibody approach used. Thus the main conclusions of the manuscript are not supported in terms of the role of ATP8A2 in LPS-induced depression.
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Summary: Both reviewers felt that the work was well done and quite convincing that LPS down regulates ATP8A2 by upregulating IFN-gamma. This is a novel and interesting finding. But both reviewers also agreed that there is insufficient evidence causally connecting the changes in ATP8A2 to behavior, and that the behavioral tests used are not sufficient to draw rigorous conclusions regarding depression-like behavior. Combined, these weaknesses lessen the impact of the findings for the field.
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