Impaired Interneuron Development in a Novel Model of Neonatal Brain Injury

Abstract

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 (SST) and calbindin (CLB) 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.

Connexin Hemichannel Mimetic Peptide Attenuates Cortical Interneuron Loss and Perineuronal Net Disruption Following Cerebral Ischemia in Near-Term Fetal Sheep

“…In the present study, cerebral ischemia in near-term fetal sheep was associated with a pattern of parasagittal cortical damage after 7 days of recovery, which included a marked reduction in the survival of cortical GAD + , parvalbumin + , calretinin + , and calbindin + interneuron populations. These findings are broadly consistent with previous studies showing loss and disrupted development of interneurons in the cerebral cortex and subcortical grey matter following HI in preterm and term fetal sheep [17,[32][33][34][35] and neonatal rodents [36][37][38][39][40][41][42][43] and following ventilatory support in preterm baboons [44]. Although there are no comparable term human data, limited pathology and imaging studies in preterm infants have shown reductions in the numbers and complexity of cortical interneurons, refs [25,45] cortical interneuron migration, [7] interneuron neurogenesis, [46] and cortical GABAergic signaling [4].…”

Intranasally Administered Exosomes from Umbilical Cord Stem Cells Have Preventive Neuroprotective Effects and Contribute to Functional Recovery after Perinatal Brain Injury

“…To support the stringency of our findings, future studies would be beneficial to further characterize the dying neurons within the subplate zone of the posterior parietal cortex to confirm their subplate neuronal identity and to differentiate them from forkhead box protein 1 (foxp1)-expressing neighboring neurons from cortical layers II–V [18]. Additionally, a very recent study showed that the loss of GABA-ergic interneurons within the prefrontal cortex in a novel mouse model of preterm brain injury lead to specific working memory deficits and neurobehavioral deficits which parallel human psychopathologies seen in preterm birth survivors [58]. Further investigations would be required to analyze whether there are also GABA-ergic interneurons among the dying cells within the parietal cortex.…”

Human 3D cellular model of hypoxic brain injury of prematurity

“…Postmortem studies have indicated a significant loss of GABAergic interneurons in premature infants 36,37 . Our current model does not include interneurons, which are born in the ventral forebrain and have to migrate dorsally to integrate into cortical circuits 38 .…”