Placental neurosteroids shape cerebellar development and social behaviour

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders 1,2. The placenta is the first functional foetal endocrine organ, but the direct impact of placental hormone loss on foetal brain in late gestation has not been empirically tested. Allopregnanolone (ALLO) is a non-glucocorticoid, progesterone derivative that acts as a positive modulator of GABA-A receptor activity3 with the potential to alter critical GABA-mediated developmental processes 4,5. To directly test the role of placental ALLO, we generated a novel mouse model in which the gene encoding the synthetic enzyme for ALLO (Akr1c14) is specifically deleted in trophoblasts using a tissue-specific Cre-Lox strategy. ALLO concentrations are significantly decreased in late gestation in placenta and brain when placental Akr1c14 is removed, indicating placenta as the primary gestational ALLO source. We now demonstrate that targeted placental ALLO loss leads to permanent changes in brain development in a sex- and regionally-specific manner. Placental ALLO insufficiency led to male-specific cerebellar white matter (WM) abnormalities characterized by excess myelination with increased myelin protein expression, similar to changes reported in boys with autism spectrum disorders (ASD)6,7. Behavioural testing of these mice revealed increased repetitive behaviour and sociability deficits, two hallmarks of ASD, only in male offspring with placental ALLO insufficiency. Notably, a strong positive correlation was seen between the cerebellar contents of myelin basic protein (MBP) and the severity of ASD-like behaviours. A single injection of ALLO during gestation was sufficient to rescue both cerebellar MBP levels and aberrant behaviours. This study reveals a new role for a placental hormone in shaping specific brain structures and behaviours, and suggests that identifying placental hormone insufficiency or preterm loss may offer novel therapeutic opportunities to prevent later neurobehavioural disorders.