Researchers found that Prozac, given during development, can reduce autism-like traits in mouse models of the disorder.
Symptoms of autism spectrum disorder (ASD) are varied but often include difficulty with socializing and exhibiting repetitive behaviors.
An estimated is diagnosed with ASD in the United States. Worryingly, the number of diagnoses made is .
Despite its prevalence, the exact causes of ASD are not yet known. Because of this, treatment options are also severely lacking.
New research carried out at the RIKEN Brain Science Institute in Japan set out to investigate the role of serotonin in the development of ASD. Led by Toru Takumi, the work is published this week in the journal Science Advances.
Genes, serotonin, and autism
Recent work has shown that individuals with ASD have a high number of genomic mutations across a range of genes. Using this knowledge, Takumi’s group designed a mouse model of ASD by duplicating one of the most common copy variations.
The resulting mice displayed some of the characteristics of ASD in humans, such as behavioral inflexibility and poor social interaction. Interestingly, these mice had lower levels of serotonin in their brains during development – something that has in humans with ASD.
“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,” said Takumi.
In their study, the Japanese team wanted to understand how lower levels of serotonin can affect the behavior of neurons and the impact that this has on behavior.
Firstly, the team demonstrated that the neurons in the brain area with highest serotonin levels were less active than in normal, control mice. Next, they studied the region of the brain that receives neurons from these particular serotonergic neurons.
Individuals with ASD are known to have abnormal responses in the sensory regions of their brain. Takumi and his team found similar discrepancies in the part of the mouse brain that deals with whisker movements.
In the ASD mouse model, rather than whisker movements being confined to discrete areas, they were spread more liberally across the sensory cortex. This overlapping of regions means that it would be harder to distinguish sensations.
The team presumed that, because there was activity in normally inactive neurons, there may be reduced inhibition. The team confirmed this theory; they found that there were “fewer inhibitory synapses” and less frequent inhibitory inputs to the sensory area.
This discovery led to the next phase of the experiment. As first author Nobuhiro Nakai explains, “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.”
Does increased serotonin alter ASD behavior?
To answer this question, the researchers used a selective serotonin reuptake inhibitor (SSRI) called fluoxetine, which is also known as Prozac. SSRIs are common drugs used to treat depression and anxiety disorders.
They gave Prozac to the mice 3 weeks after birth, a point in time when serotonin is known to be reduced in the mouse model. Sensory neurons in the mice treated with SSRIs did, as expected, exhibit more normal inhibitory responses.
Once the inhibitory/excitatory balance had been brought back in line, the team tested to see whether or not the mice’s behavior would also change in line.
To examine this, they gave the mice a choice of spending time near an empty cage, or near a cage that housed an unknown mouse. Normally, mice choose to spend more time next to a cage with an unknown rodent. ASD model mice, however, choose to spend time next to the empty cage.
The ASD mice given Prozac during development chose to spend more time close to the unknown mouse. Also, ASD mouse pups produced more vocalizations, which is a measure of anxiety, while those given Prozac did not.
The findings may offer a new avenue of research into ASD and potential treatments. Of course, there will need to be much more research, as Takumi explains:
“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.”
Although the hunt for ASD treatments will be ongoing for many years to come, the current findings offer fresh hope.