Prenatal Valproic Acid Exposure Impairs Offspring Cognition Through Disturbing Interneuron Development

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Gestational exposure to valproic acid (VPA) is linked to cognitive deficits in offspring.
• The precise mechanisms by which VPA impacts neurodevelopment remain incompletely understood.

Purpose of the Study:

• To investigate if prenatal valproic acid (VPA) exposure disrupts interneuron development, leading to cognitive impairment in offspring.
• To identify specific interneuron subtypes affected by VPA exposure and explore molecular changes.

Main Methods:

• Established a prenatal VPA exposure model in pregnant mice.
• Utilized reporter mice to track cortical interneuron development in the cortex and hippocampus.
• Conducted behavioral tests for cognition and anxiety, alongside RNA-Seq for molecular analysis.

Main Results:

• Prenatal VPA exposure induced anxiety in male offspring and impaired memory when administered on gestational day 12.5.
• VPA disrupted the distribution of cortical interneurons, with specific effects on somatostatin-positive neurons.
• RNA-Seq revealed significant alterations in biological processes related to ion homeostasis.

Conclusions:

• Prenatal VPA exposure during critical neurodevelopmental periods impairs offspring cognition by disrupting interneuron migration and differentiation.
• These findings highlight the subtype-specific vulnerability of interneurons to VPA and offer insights into VPA's neurodevelopmental impact.