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GR/Ahi1 regulates WDR68-DYRK1A binding and mediates cognitive impairment in prenatally stressed offspring
Bin Wei1, Haixia Shi2, Xi Yu1
1Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Insights
Prenatal stress impairs offspring cognition by reducing Ahi1 levels, affecting synaptic plasticity. GR antagonist RU486 improved cognitive function and synaptic plasticity in offspring exposed to prenatal stress.
Area of Science:
- Neuroscience
- Developmental Psychology
- Molecular Biology
Background:
- Maternal stress during pregnancy is linked to offspring behavioral and mental health issues.
- The precise mechanisms by which prenatal stress impacts offspring neurodevelopment remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying prenatal stress-induced cognitive impairment in offspring.
- To investigate the role of Ahi1 and glucocorticoid receptor (GR) signaling in mediating these effects.
Main Methods:
- Investigated the effects of prenatal stress (PNS) on offspring Ahi1 levels, synaptic plasticity, and cognitive function.
- Utilized molecular assays to examine the interactions between Ahi1, GR, WDR68, and DYRK1A.
- Administered RU486, a GR antagonist, to assess its impact on PNS-induced deficits.
Main Results:
- PNS led to reduced Ahi1, impaired synaptic plasticity, and cognitive deficits in offspring.
- PNS disrupted the Ahi1/GR complex, promoting DYRK1A activity and further impairing plasticity.
- RU486 treatment reversed cognitive impairment and restored synaptic plasticity in PNS offspring by increasing Ahi1/GR levels.
Conclusions:
- Prenatal stress-induced cognitive impairment is mediated by the dysregulation of the Ahi1/GR signaling pathway.
- Targeting GR signaling with antagonists like RU486 may offer therapeutic potential for mitigating the neurodevelopmental consequences of prenatal stress.
Abstract:
Accumulating research shows that prenatal exposure to maternal stress increases the risk of behavioral and mental health problems for offspring later in life. However, how prenatal stress affects offspring behavior remains unknown. Here, we found that prenatal stress (PNS) leads to reduced Ahi1, decreased synaptic plasticity and cognitive impairment in offspring. Mechanistically, Ahi1 and GR stabilize each other, inhibit GR nuclear translocation, promote Ahi1 and WDR68 binding, and inhibit DYRK1A and WDR68 binding. When Ahi1 deletion or prenatal stress leads to hyperactivity of the HPA axis, it promotes the release of GC, leading to GR nuclear translocation and Ahi1 degradation, which further inhibits the binding of Ahi1 and WDR68, and promotes the binding of DYRK1A and WDR68, leading to elevated DYRK1A, reduced synaptic plasticity, and cognitive impairment. Interestingly, we identified RU486, an antagonist of GR, which increased Ahi1/GR levels and improved cognitive impairment and synaptic plasticity in PNS offspring. Our study contributes to understanding the signaling mechanisms of prenatal stress-mediated cognitive impairment in offspring.
