Maternal Immune Activation Induces Adolescent Cognitive Deficits Preceded by Developmental Perturbations in Cortical
Rebecca M Woods1, Jarred M Lorusso1, Isabella Harris1
1Division of Evolution, Infection and Genomics, School of Biological Sciences, Manchester Academic Health Science Centre, Faculty of Biology, Medicine & Health, University of Manchester, Manchester M139PL, UK.
Insights
Maternal immune activation (MIA) in utero impairs Reelin signaling, leading to cognitive deficits in offspring. This study identifies Reelin pathway dysregulation as a key mechanism in neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Psychiatry
Background:
- Maternal immune activation (MIA) in utero is linked to increased schizophrenia risk.
- Reelin signaling is crucial for neuronal development and cognitive function.
- The impact of MIA on Reelin expression and cognitive deficits is not well understood.
Purpose of the Study:
- To investigate the effects of MIA on Reelin signaling during cortical development.
- To explore the relationship between Reelin dysregulation and cognitive deficits in offspring.
- To identify potential therapeutic targets for MIA-induced neurodevelopmental disorders.
Main Methods:
- Utilized a rat model of maternal immune activation (MIA).
- Assessed object-location memory in adolescent offspring.
- Measured Reelin (Reln) gene expression and downstream signaling components in the prefrontal cortex.
Main Results:
- MIA offspring exhibited object-location memory deficits.
- Prenatal and adult prefrontal cortex showed reduced Reelin expression in MIA offspring.
- Developmental disturbances in gene/protein expression and DNA methylation of downstream targets were observed.
Conclusions:
- MIA-induced Reelin signaling dysregulation contributes to prefrontal cortex-mediated cognitive deficits.
- Altered NMDA receptor function and impaired long-term potentiation are implicated.
- Targeting Reelin signaling during a specific developmental window may offer therapeutic potential.
Abstract:
Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.
