TY - JOUR T1 - Impaired interneuron development in a novel model of neonatal brain injury JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0300-18.2019 SP - ENEURO.0300-18.2019 AU - Helene Lacaille AU - Claire-Marie Vacher AU - Dana Bakalar AU - Jiaqi J. O’Reilly AU - Jacquelyn Salzbank AU - Anna A Penn Y1 - 2019/01/31 UR - http://www.eneuro.org/content/early/2019/01/30/ENEURO.0300-18.2019.abstract N2 - Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism and schizophrenia. A common feature of these psychiatric disorders is prefrontal cortex (PFC) inhibitory circuit disruption due to GABAergic interneuron alteration. Cortical interneurons are generated and migrate throughout late gestation and early infancy, making them highly susceptible to perinatal insults such as preterm birth. Term and preterm PFC pathology specimens were assessed using immunohistochemical markers for interneurons. Based on the changes seen, a new preterm encephalopathy mouse model was developed to produce similar PFC interneuron loss. Maternal immune activation (MIA; modeling chorioamnionitis, associated with 85% of extremely preterm births) was combined with chronic sublethal hypoxia (CSH; modeling preterm respiratory failure), with offspring of both sexes assessed anatomically, molecularly and neurobehaviorally. In the PFC examined from the human preterm samples compared to matched term samples at corrected age, a decrease in somatostatin and calbindin interneurons was seen in upper cortical layers. This pattern of interneuron loss in upper cortical layers was mimicked in the mouse PFC following the combination of MIA and CSH, but not after either insult alone. This persistent interneuron loss is associated with postnatal microglial activation that occurs during CSH only after MIA. The combined insults lead to long-term neurobehavioral deficits which parallel human psychopathologies that may be seen after extremely preterm birth. This new preclinical model supports a paradigm in which specific cellular alterations seen in preterm encephalopathy can be linked with a risk of neuropsychiatric sequela. Specific interneuron subtypes may provide therapeutic targets to prevent or ameliorate these neurodevelopmental risks.Significance Statement Growing evidence suggests that a common component of psychiatric disorders is damage to inhibitory neurons. In the frontal lobe, these neurons continue to develop during late gestation and infancy, predisposing preterm survivors to neurobehavioral disorders and/or cognitive impairment. Preventing neuronal damage depends on having accurate models of preterm brain injury with well-defined outcome measures that can be examined in both small animals and humans. In this study, interneuron number were assessed in term and preterm human frontal brain tissues and in a novel multifactorial model that combines prenatal inflammation with postnatal hypoxia resulting in long-term inhibitory neuron loss. This new model was validated through anatomical and functional assessments that directly translate to human measures. ER -