Olfactory Bulb Neurons Tied to Autism Hypersensitivity in Mouse Study

DGIST identified causes of hypersensitivity accompanied by neurodevelopmental disorder such as autism-spectrum disorder (ASD). This is expected to make contributions to the early diagnosis of sensory-defective symptom brought with neurodevelopmental disorder and cancer as well as the improvement of anti-cancer drug side effects.

DGIST announced that the Department of Brain and Cognitive Sciences found the important mechanism of the Abl1 gene, which is involved in the early developmental stage of inhibitory neuron for forming normal sensory circuits.

Before formation of cognitive or verbal neural circuits in brain development, sensory circuits are developed explosively for one year after birth. An ASD with cognitive and sensory defects is caused if inhibitory neural circuit is not formed properly due to genetic and environmental factors during the brain development. While studies on ASD treatment have focused on the abnormal development of inhibitory neurons related to cognitive disorder, no sufficient research has been made on the specific causes and mechanisms of sensory defects that occur first.

The DGIS research team discovered for the first time that Abl1 gene is expressed and activated explosively during the early development of inhibitory neurons in the mouse olfactory bulb. They also learned that if the expression or activation of Abl1 is inhibited using lenti-virus, inhibitory neurons cannot reach their cell layers accurately due to structural defects.

A candidate gene of ASD, Abl1 is also well-known to cause cancer. If Chronic Myelogenous Leukemia (CML) patients aged 2-9 with active brain development intake target anti-cancer drug Gleevec (Imatinib), an Abl1 deactivator, more than 60% of them show sensory related-side effects such as olfactory hallucination. Based on this, the research team confirmed that the inhibition of Abl1 expression and activation greatly increased the olfactory sensitivity of mouse as the side effect of Gleevec intake.

The research team also discovered that, using proteomics, Abl1 temporarily phosphorylated doublecortin (Dcx), a cytoskeletal protein that plays a crucial role in the structural development of brain. This proposed that Abl1 regulates the dynamic of microtubule with a new signal transmission system between Abl1 and Dcx.

Professor Cheil Moon in the Department of Brain and Cognitive Sciences at DGIST said "We found a very important clue to understand the mechanism of hypersensitivity appearing in neurodevelopmental disorder or cancer disease, which are yet to be known clearly. We hope to see follow-up research to overcome other sensory disorders based on our research."

Reference

Kim et al. (2020) Timely Inhibitory Circuit Formation Controlled by Abl1 Regulates Innate Olfactory Behaviors in Mouse. Cell Reports. DOI: https://doi.org/10.1016/j.celrep.2019.12.004

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