Maternal immune activation impairs neurodevelopment in offspring via ASK1/MAPK-mediated apoptotic disruption during...

The neurodevelopmental hypothesis of schizophrenia posits that early brain developmental abnormalities constitute its core pathological basis. However, the mechanisms by which environmental risk factors regulate specific molecular pathways, leading to long-term behavioral abnormalities, remain incompletely elucidated. This study aims to investigate whether maternal immune activation (MIA) disrupts the ASK1/MAPK signaling pathway in offspring during early development, alters neuronal apoptosis homeostasis, and ultimately mediates the emergence of schizophrenia-like phenotypes.

A MIA rat model was established. In offspring, at multiple postnatal developmental time points (P1, P7, P14, P21), the protein expression and phosphorylation levels of ASK1, p-p38, and p-JNK in the hippocampus and prefrontal cortex were detected. Additionally, the expression of apoptosis-related proteins Bax and Bcl-2 was measured. Neuronal structure was assessed using Nissl staining, and behavioral tests were performed.

MIA offspring exhibited anxiety-like behaviors, cognitive deficits, and sensory gating impairments. The ASK1/MAPK pathway demonstrated spatiotemporal-specific disturbances: hippocampal ASK1 activity showed a triphasic dynamic abnormality, while the prefrontal cortex displayed biphasic suppression. These pathway disruptions were closely associated with brain region-specific imbalances in apoptosis homeostasis. The Bax/Bcl-2 ratio in the prefrontal cortex exhibited biphasic oscillations, whereas the hippocampus showed selective suppression of apoptotic activity at P7 and P21. Nissl staining further confirmed neuronal structural damage in MIA offspring.

This study first demonstrates that MIA induces spatiotemporal-specific ASK1/MAPK pathway disturbances, thereby altering neuronal apoptosis homeostasis during development and ultimately leading to neuronal structural damage and schizophrenia-like behavioral phenotypes. The differential mechanisms observed in the hippocampus and prefrontal cortex in response to MIA provide new experimental evidence for understanding the neurodevelopmental origins of schizophrenia, suggesting that the ASK1/MAPK pathway may serve as a critical bridge connecting early environmental stress with long-term neuropsychopathological phenotypes.