Experimental drugs rewire brain connections in autism

New research from the University of Texas Southwestern in Dallas has identified two potential new treatments for autism spectrum disorder, targeting the impact of a faulty gene on neural communication.

Autism — which is often used as an umbrella term for autism spectrum disorder (ASD) — is characterized by repetitive behaviors, impaired social communication, and very focused interests.

According to estimates from the Centers for Disease Control and Prevention (CDC), around 1 in 68 children in the United States have been diagnosed with ASD.

Treatments for ASD are often focused on addressing the behavioral symptoms and helping people with the disorder to learn better communication strategies. So far, relatively few efforts have targeted the biological causes of autism.

Now, researchers from the University of Texas Southwestern in Dallas are exploring the route of learning more about these biological factors in order to address them directly.

The study, led by Dr. Craig Powell, has identified two potential treatments that could restore the neurotransmission processes affected by the absence of a gene known as KCTD13.

Dr. Powell and team published the results of their research in the journal Nature.

Missing gene 'impairs brain function'

The KCTD13 gene encodes a protein with the same name, and previous studies have linked its expression level with abnormal brain size, arguing that "[b]oth the loss and the gain of [the chromosomal segment that contains this gene] confer a significant risk of autism and developmental delay."

Dr. Powell and colleagues' research, however, revealed that KCTD13 plays an entirely different role: it is not tied not to brain size but to synaptic transmission, or neurotransmission. This is the neurons' ability to transmit information.

"[W]e were quite surprised that the Kctd13 deletion did not result in increased brain size, increased embryonic cell proliferation, and changes in migration," Dr. Powell told Medical News Today, explaining that he and his team were expecting to confirm the results of previous studies.

The researchers also identified drugs that may be able to reverse the faulty connectivity that comes as a result of this gene's deletion.

"The deletion of this gene impairs brain function in a major way, and we found a way to repair the damage. But we have more work to do before we try these treatments on people. The findings give us a clue as to what pathways are altered and where to look."

Dr. Craig Powell

Dr. Powell and team used mice to investigate what the KCTD13 protein actually does, as well as what role it plays in autism.

In their experiments, they deleted the gene that encoded the protein in mice, and noted that its absence halved the number of synaptic connections in the animals' brains.

The researchers noticed that in the absence of KCTD13, the levels of a protein known as RhoA increase, which impairs synaptic transmission.

In its normal expression, KTCD13 helps to regulate this protein, allowing neurons to communicate freely.

Scientists test drugs with high potential

To counteract the effect of the gene deletion, Dr. Powell and tested different types of RhoA-inhibiting drugs: Rhosin and Exoenzyme C3.

This approach was successful, restoring normal synaptic transmission in under 4 hours.

The relatively short time it took for the drug to show its effect again took the scientists by surprise.

"We were also surprised that incubation of brain slices in RhoA inhibitors could reverse synaptic abnormalities within the relatively short time frame of a few hours," Dr. Powell told MNT.

Still, the positive effects were only visible in the short term, so the researchers are intersted in verifying how often these drugs would have to be administered in order to maintain their impact.

"We demonstrated that incubation of these drugs on acute brain slices could restore synaptic function acutely in the short-term," Dr. Powell explained.

"In the future," he added, "we hope to perform experiments to determine if long-term in vivo administration of these or similar drugs might also lead to long-lasting restoration of synaptic function in the brain."

The researchers note that Exoenzyme C3 is currently being tested in clinical trials for the treatment of spinal cord injury. If successful, they hope that these trials will smoothen the path for further tests of the drug's potential in ASD treatments, as well.

In the meantime, Dr. Powell and team would like to focus their efforts on additional studies of the KCTD13 gene, whose complex role in the context of neurotransmission is yet to be fully understood.

"There are several next steps from this research," Dr. Powell told us. "First, we would like to know if RhoA levels are altered in [...] mouse models or patients [lacking the chromosomal segment that contains KCTD13]."

"Second, we would like to determine if the abnormal locomotor behavior [observed] in the Kctd13 mice might be rescued by treatment of the whole animal with RhoA inhibitors," he added.

Finally, the researcher expressed an interest "in looking at other genetic models of autism that are predicted to alter the RhoA pathway."