Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. Those include Fetal Alcohol Spectrum Disorders (FASD) with a wide range of cognitive deficiencies including impaired motor skill development. While these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We have previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells alter gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlates with motor learning deficits in the mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a novel intervention for learning disabilities in FASD.

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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.

BACKGROUND AND PURPOSEClassic H1 histamine receptor (H1R) antagonists are non-selective for H1R and known to produce drowsiness. Modern antihistamines are more selective for H1R, and are 'non-drowsy' presumably due to reduced permeability through the blood-brain barrier. To characterize both histaminergic sleep regulation and the central actions of antihistamines, in the present study we analysed the effect of classic and modern antihistamines on rats' sleep using continuous i.c.v. infusions. EXPERIMENTAL APPROACHEffects of classic (d-chlorpheniramine; d-CPA) and second-generation (cetirizine) antihistamines on sleep were compared after i.p. injections or continuous i.c.v. infusions into rats. Fluorescent cetirizine/DBD-pz was synthesized to trace the approximate distribution of cerebral cetirizine. Furthermore, the effects of H1R antagonists on cultured preoptic neurons were examined using calcium imaging. ) increased drowsiness but not non-REM sleep, whereas the same i.c.v. infusions of cetirizine significantly increased non-REM sleep, abolished REM sleep, and decreased wakefulness for more than 10 h. The medial preoptic area contained the greatest fluorescent labelling after i.c.v. cetirizine/ DBD-pz infusions. Histamine-induced Ca 2+ increases in medial preoptic neurons were blocked by d-CPA or cetirizine, whereas d-CPA, but not cetirizine, increased Ca 2+ irrespective of antihistaminergic activity at Ն100 mM. KEY RESULTS d-CPA CONCLUSION AND IMPLICATIONSThe excitatory action of d-CPA may explain the seemingly inconsistent actions of d-CPA on sleep. Cerebral H1R inhibition by cetirizine induces synchronization of cerebral activity and prolonged, continuous slow-wave sleep.

Excessive alcohol consumption results in significant changes in gene expression and isoforms due to altered mRNA splicing. As such, an intriguing possibility is that disturbances in alternative splicing are involved in key pathological pathways triggered by alcohol exposure. However, no resources have been available to systematically analyze this possibility at a genome-wide scale. Here, we performed RNA sequencing of human fetal cortical slices that were obtained at the late first trimester and exposed to ethanol or control medium. We report 382 events that were identified as changes affecting the ratio of splicing isoforms in the ethanol-exposed fetal human cortex. Additionally, previously unreported novel isoforms of several genes were also identified. These results provide a broad perspective on the post-transcriptional regulatory network underlying ethanol-induced pathogenesis in the developing human cortex.