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Primary cilia safeguard cortical neurons in neonatal mouse forebrain from environmental stress-induced dendritic degeneration

Significance External agents, such as alcohol and ketamine, are known to affect perinatal brain development and eventually cause a variety of severe psychopathological consequences. However, the mechanisms of possible neuronal defense against these agents are not well understood. We sought to elucidate the molecular details of the role of primary cilia in this complex process. Our results show that primary cilia protect dendrites of immature cortical neurons via insulin-like growth factor 1 receptor and downstream Akt signaling. These results provide insight into the pathogenesis of consequences that follow exposure to toxic substances. The developing brain is under the risk of exposure to a multitude of environmental stressors. While perinatal exposure to excessive levels of environmental stress is responsible for a wide spectrum of neurological and psychiatric conditions, the developing brain is equipped with intrinsic cell protection, the mechanisms of which remain unknown. Here we show, using neonatal mouse as a model system, that primary cilia, hair-like protrusions from the neuronal cell body, play an essential role in protecting immature neurons from the negative impacts of exposure to environmental stress. More specifically, we found that primary cilia prevent the degeneration of dendritic arbors upon exposure to alcohol and ketamine, two major cell stressors, by activating cilia-localized insulin-like growth factor 1 receptor and downstream Akt signaling. We also found that activation of this pathway inhibits Caspase-3 activation and caspase-mediated cleavage/fragmentation of cytoskeletal proteins in stress-exposed neurons. These results indicate that primary cilia play an integral role in mitigating adverse impacts of environmental stressors such as drugs on perinatal brain development.