Placental Allopregnanolone is Essential for Development of Cortical GABAergic Signaling

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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.