AsianScientist (July 3, 2017) – Scientists at the RIKEN Brain Science Institute have linked early serotonin deficiency to several symptoms that occur in autism spectrum disorder (ASD). Published in Science Advances, the study showed that increasing serotonergic activity in the brain during early development led to more balanced brain activity and improved social behavior in a mouse model of ASD.
The causes and symptoms of ASD are varied, and many people with ASD have many genomic mutations. Previously, Dr. Toru Takumi’s group generated a mouse model of ASD by duplicating, in mice, one of the most frequent copy variations found in people with ASD. These mice show many behavioral symptoms of ASD, including poor social interaction and low behavioral flexibility, and have reduced levels of serotonin in the brain during development.
“Although abnormalities in the serotonin system have been thought to be part of the ASD pathophysiology, the functional impact of serotonin deficiency in ASD was totally unknown,” Group leader Takumi explained. “Our work shows that early serotonergic intervention rescues regional excitatory/inhibitory abnormalities in the brain as well as behavioral abnormalities.”
In normal mice, specific whisker movements are tightly mapped across the sensory region of the brain. In contrast, calcium imaging of the brains of ASD model mice showed that a given whisker movement activated a much larger region of the sensory cortex. This means that the responses of neighboring brain regions were more overlapped, indicating reduced inhibitory activity in the brains of ASD model mice—in essence, an abnormality in cortical excitatory/inhibitory balance was prevalent.
“Because the sensory region was receiving abnormally low serotonin input, we reasoned that giving infant mice serotonin therapy might reduce the imbalance and also rescue some of the behavioral abnormalities,” noted Dr. Nobuhiro Nakai, the first author of the paper.
To test this hypothesis, the team administered a selective serotonin reuptake inhibitor (SSRI) to infant mice during the first three weeks after birth. Typically, ASD mouse pups display anxiety by vocalizing more than normal pups. This abnormal behavior was rescued by the SSRI treatment.
Importantly, behavioral improvements from SSRI treatment extended into adulthood. The social behavior of adult mice was measured by exposing mice to a cage with an unknown mouse or an empty cage. Normal mice spent more time near the cage with the unknown mouse, while the ASD model mice preferred the empty cage. After the SSRI treatment, ASD model mice spent more time around the cage with the unknown mouse.
Researchers also found that sensory neurons in the ASD model mice treated with the SSRI showed more normal inhibitory responses, which improved the excitatory/inhibitory balance. These findings suggest that serotonin may have be potentially therapeutic for discrete ASD symptoms.
Looking toward the future, Takumi is optimistic, yet cautious.
“Our genetic model for ASD is one of many and because the number of genetic mutations associated with ASD is so high, we need to investigate differences and common mechanisms among multiple genetic ASD models. Additionally, before we can administrate SSRIs to patients with ASD, we must study the effects of SSRIs in more detail, especially because adverse effects have been reported in some animal studies.”
The article can be found at: Nakai et al. (2017) Serotonin Rebalances Cortical Tuning and Behavior Linked to Autism Symptoms in 15q11-13 CNV Mice.
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Source: RIKEN; Photo: Ben Mills/Wikimedia Commons/CC0.
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