PROJECT SUMMARY
Preterm birth (PTB), occurring in 10% of all births, is highly correlated with negative neurologic outcomes such
as autism, schizophrenia, and other psychiatric disorders. In all PTBs, the placenta is lost prematurely, which
may have potentially harmful consequences. The placenta is a critical component of healthy pregnancy that
supplies the developing fetus with essential hormones not yet made by the fetus, including the neurosteroid
Allopregnanolone (ALLO). Thus, placental loss due to PTB may contribute to disrupted neurodevelopment, in
part through loss of critical placental hormones. ALLO levels peak in mother and fetus during pregnancy due to
placental synthesis. Since ALLO can act as a potent, positive allosteric modulator of GABAA receptors (GABAA-
R) and simultaneously regulate their expression, placental ALLO exposure may modulate fetal GABAergic
systems. During development, these GABAergic synapses are the first to become functional and their excitatory
actions facilitate activity depended neuronal maturation and integration. To investigate ALLO's effects on early
GABAergic signaling, we created a model of placental ALLO loss - the Akr1c14Cyp19aKO mouse (plKO). This
model is uniquely tissue and hormone specific, making it the ideal system to test the hypothesis: placental
ALLO loss disrupts the development of the GABAergic systems in the fetal somatosensory cortex with
consequences that persist into adulthood. Preliminary results from the somatosensory cortex of plKOs reveal
decreases in upper-layer neurons and these mice exhibit neurobehavioral deficits in somatosensory function
that resemble those seen in human preterm survivors. plKOs display altered inhibitory postsynaptic currents
(IPSCs) in the mature somatosensory cortex, as well as early disruptions to GABAA-R subunits and the chloride
ion transporter KCC2, that regulates the excitatory-to-inhibitory switch of GABA. Importantly, many of these
differences appear to be sex-dependent. Collectively, the literature and our data indicate an interaction between
ALLO and GABAergic signaling that may be sex-specific, but the timing and extent of the disruption is unknown.
To determine the specific role of placental ALLO on the development of GABAergic signaling, I will investigate
the following aims: 1) Molecularly characterize the effect of placental ALLO loss on GABAergic signaling in the
developing cortex; and 2) physiologically determine the sex-specific consequences of placental ALLO loss on
neural activity in the neonatal cortex. Through successful completion of these aims, I will receive outstanding
academic and laboratory training in comprehensive hypothesis testing and I will acquire critical analysis skills
that are essential as I prepare for a career in neuroscience research.