HONG KONG – Scientists at the Riken Brain Science Institute (BSI) have linked low levels of the neurotransmitter serotonin to the symptoms of autism spectrum disorder (ASD) in young mice, suggesting selective serotonin reuptake inhibitors (SSRIs) may have a role in treating autism in humans.

Published in the June 21, 2017, edition of Science Advances, the study also found that increased brain serotonergic levels during early development were associated with more balanced brain activity and improved sociability in a mouse model of ASD.

While various treatments have been tried for autism, "no effective drugs are currently available, hence the urgent need for new agents for the treatment of ASD," said lead researcher Toru Takumi, professor and senior team leader of the Laboratory for Mental Biology at Riken BSI, of Wako, Japan.

"Although the link between ASD and serotonin is well known, the pathophysiology underlying this remains totally unknown, as does the functional impact of serotonin deficiency in ASD," Takumi told BioWorld.

However, in their new study, "we showed that early serotonergic intervention rescues regional excitatory/inhibitory abnormalities in the brain as well as behavioral abnormalities."

While there are multiple causes and symptoms of ASD, many ASD patients also have genetic mutations. Takumi's group had previously developed a mouse model of ASD by replicating one of the most common of these mutations.

The mouse models display many ASD symptoms, including poor social interaction and low behavioral adaptability. They also have reduced brain serotonin levels during development, as do ASD patients.

The researchers examined how the mutation affected mouse brain neurons and behavior. After determining that the part of the brain that contains the highest amount of serotonergic neurons was less active in ASD models than in wild-type animals, they examined a sensory region of the brain receiving input from such neurons.

"We showed that the dorsal raphe nucleus area was less active in our mouse model electrophysiologically, using slices of raphe nuclei and positron emission tomography (PET) with fluoxydeoxyglucose (FDG) imaging," explained Takumi.

The Riken researchers also found similar abnormalities to those often seen in the sensory regions of ASD patients, in the brain region of the model mice that detects whisker movement.

While specific whisker movements are normally tightly mapped across this region, transcranial calcium imaging showed that a given movement activated a larger region of the sensory cortex in the ASD model mice, suggesting neighboring responses were more overlapped, reducing the ability to distinguish sensations.

That indicates that normally inactive neurons were active, suggesting reduced inhibition. That was confirmed using immunohistochemistry with synaptic markers in somatosensory cortex slices to show the ASD model mice had fewer inhibitory synapses and a lower frequency of sensory inhibitory inputs, suggesting an abnormal cortical excitatory and inhibitory balance.

"Combined with in vivo electrophysiological data, we thought that change of the response shown by transcranial calcium imaging might be due to impairment of the brain's inhibitory systems," noted Takumi.

Because the sensory cortex was receiving abnormally low serotonin input, the researchers reasoned that giving infant mice serotonin therapy might reduce the imbalance and rescue some of the behavioral abnormalities.

Therefore, in order to test this hypothesis, in collaboration with Hidenori Suzuki, a professor in the Department of Pharmacology at Tokyo's Nippon Medical School, they administered the SSRI Prozac (fluoxetine, Eli Lilly and Co.) to infant mice during the first three weeks postnatally, when reduced serotonin was also seen in the model mice.

They found that sensory neurons in the model mice treated with the SSRI showed more normal inhibitory responses, which improved the excitatory/inhibitory balance.

Prozac was also shown to improve social behavior of adult model mice, as measured by mice being exposed to a cage containing an unknown mouse, which is favored by normal animals, or to an empty cage, as preferred by the ASD models.

Following SSRI treatment, ASD mice spent more time near the unknown mouse cage, suggesting more normal social behavior. "Our mouse model spent more time near the stranger mouse after SSRI treatment," noted Takumi.

Improved communication behavior was also seen in the ASD model mouse pups after treatment. While these displayed anxiety by producing more vocalizations than normal, this behavior was rescued by the SSRI, suggesting serotonin may be therapeutic for certain ASD symptoms in humans.

"The increased number of ultrasonic vocalizations (USVs) was decreased to pretreatment levels in a dose-dependent manner," said Takumi. However, "this change of USV phenotypes might also reflect rescue of anxiety," he conceded.

Regarding future management of ASD in humans, "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," said Takumi.

"Additionally, before we can administer SSRIs to ASD patients, we must study their effects in more detail, especially as adverse effects have been reported in some animal studies. We'd also like to understand better the neural circuits involved in social behavior."