Therapeutics Targeting cAMP Signaling Can Help Improve Sensory Perception in Patients with Fragile X Syndrome

Therapeutics Targeting cAMP Signaling Can Help Improve Sensory Perception in Patients with Fragile X Syndrome

Medicine that regulates cyclic adenosine monophosphate (cAMP) signaling can help correct defects in processing of sensory information in a fruit fly model of fragile X syndrome, a new study shows.

The study, “Stress Odorant Sensory Response Dysfunction in Drosophila Fragile X Syndrome Mutants,” was published in the journal Frontiers in Molecular Neuroscience.

Ninety percent of people with intellectual disability and autism spectrum disorder present with a symptom known as sensory processing dysfunction (SPD) — a condition in which the brain has trouble receiving and responding to information that comes in through the senses.

SPD affects multiple senses, including hearing, touch, sight, and taste. As an example, some people with ASD will perceive sound to be much louder than it is, which will affect their behavior. As a response, they will either block their ears or become increasingly anxious.

Fragile X syndrome — caused by a deficiency in the fragile x mental retardation protein (FMRP) due to mutations in the FMR1 gene — is the single most common cause of intellectual disability and autism spectrum disorder. Patients with fragile X frequently present with SPD, which has a major impact on their ability to function.

Drosophila (also known as fruit flies) have a similar gene to the human FMR1 — known as dfmr1.

Fruit flies with mutations in the dfmr1 gene present with circadian (the 24-hour internal clock), cognitive, and social defects similar to those seen in people with fragile X. However, little is known about the response to sensory signals in dfmr1 mutant flies.

Fruit flies emit Drosophila stress odorant (dSO) — a warning signal that communicates to other flies they have been subjected to electrical or mechanical stress. This makes normal “wild-type” fruit flies exhibit a robust avoidance behavioral response.

In order to adequately respond to dSO, Drosophila must be able to correctly perceive a sensory stimulus and respond accordingly.

In this study, researchers used a robust behavioral assay for sensory processing of flies’ dSO to gain a better understanding of the molecular basis of SPD in fragile X.

They found that dfmr1 mutant flies had significant defects in responding to dSO compared to control flies. Interestingly, there were no defects in dSO emission in dfmr1 mutant flies, indicating that “FMRP is involved in sensory processing and not emission of dSO.”

Next, researchers determined whether expression of dfmr1 in two higher-order brain processing centers — mushroom bodies and the central complex — are involved in dSO sensory processing. Previous studies had shown that FMRP was required in mushroom bodies for olfactory memory and that this brain area was required for carbon dioxide avoidance response in the context of food deprivation or food-related odors.

Results revealed that dfmr1 expression is required in mushroom bodies for dSO processing.

Researchers then explored whether pharmacological interventions could improve mutant flies’ avoidance response and which cellular pathways were related to the dSO defects in dfmr1 mutant flies.

A signaling pathway known as cyclic adenosine monophosphate (cAMP) signaling was found to be activated after exposure to dSO in non-mutant flies. cAMP is a messenger molecule important in many biological processes, and cAMP signaling dysregulation is linked to fragile X early on in people.

Importantly, there are several medicines that can regulate cAMP signaling, such as dipyridamole — used to reduce the risk of blood clots — and lithium. Administration of these therapies significantly improved defects in dSO processing in dfmr1 mutant flies.

“To our knowledge, this is the first time that dSO defects are rescued pharmacologically in a post-natal setting in dfmr1 mutants. This is a promising avenue for individuals with [fragile X] suffering of SPD as both lithium and dipyridamole are FDA-approved drugs,” researchers wrote.

The team found that several genes involved in intellectual disability and autism spectrum disorders are also linked to cAMP signaling. “This raises the need for high-throughput (automated large-scale) but clinically relevant systems to test not only multiple candidate drugs, but several genes,” researchers said.

“As there is pre-clinical evidence showing a conserved deficit of cAMP across species in [fragile X] and recent evidence of improvement of cognitive symptoms in fly and mouse models of [fragile X] with PDE4 inhibitors, our results underline the importance of a symptom-specific approach in … ASD pharmacological intervention testing,” researchers said.

“Moreover, PDE-specific inhibitors are currently undergoing clinical trial for behavioral defects in FXS and it may be interesting to assess improvement in SPD,” they concluded.

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