Linking placental dysfunction, cerebellar white matter alterations and social behavior deficits in a novel mouse model
- Awarded: 2018
- Award Type: Pilot
- Award #: 572832
Preterm birth occurs in approximately 10 percent of all births worldwide and is a major perinatal risk factor for autism spectrum disorder (ASD). Early environmental insults that occur with preterm birth or due to a compromised in utero environment may lead to ASD by altering early neurodevelopmental trajectories. Yet the mechanisms linking ASD and prematurity are largely unknown. One major consequence of preterm birth is the abrupt loss of the placenta.
Anna Penn’s laboratory is investigating the relationship between a potent neuroactive steroid made by the placenta during late gestation (allopregnanolone [ALLO]) and neurodevelopmental impairments using a novel mouse model in which the gene encoding the enzyme responsible for ALLO production (Akr1c14) is specifically deleted from the placenta. ALLO is a GABAergic modulator, and its loss could substantially alter essential GABAergic activation, disrupting normal development.
Preliminary findings from Penn’s group suggest an unexpected connection between preterm brain injury due to placental dysfunction, cerebellar white matter (WM) alterations and features of ASD in a placenta-specific Akr1c14 (Akr1c14pl) knockout mice. Specifically, 1) cerebellar WM alterations were identified in male Akr1c14pl knockout mice using an unbiased transcriptomic approach and confirmed histologically; 2) behavioral testing on these mice revealed social impairments and increased repetitive behaviors; and 3) there is significant overlap (91 genes) in the cerebellar dysregulated transcripts in Akr1c14pl knockout male mice and ASD risk genes from the SFARI Gene database.
The current project will test the hypothesis that placental ALLO loss increases the risk of developing ASD-like traits in male offspring via cerebellar WM abnormalities and subsequent connectivity impairments by 1) defining how placental ALLO loss impairs cerebellar myelination in male Akr1c14pl knockout mice using state-of-the-art microscopy techniques (super-resolution nanoscopy and whole cerebellum multiphoton microscopy) and 2) investigating cortico-cerebellar circuit changes after placental ALLO loss using functional mapping tools (in vivo optogenetics and quantitative magnetic resonance imaging). WM changes and circuitry in Akr1c14pl knockout mice will be compared to mouse models of ASD risk genes (such as Shank3 and En2) to identify common circuits that are fundamental to the expression of behavioral deficits relevant to ASD, no matter the cause of their alteration — environmental, genetic or the two combined. New targets in the placenta or brain that are amenable to hormone supplementation may be identified, allowing early treatment opportunities for fetuses at high risk for ASD.