Dartmouth's Luikart: Results of autism research 'tells us we're really on to something'

Findings from a recent study into the neurobiological underpinnings of autism spectrum disorders (ASD) have resulted in a potentially significant breakthrough. The study offers crucial findings into the role of mutated genes in ASD and suggests potential treatment avenues that could revolutionize patient care. 

The study, "Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss," was published this past November in Cell Reports. In the study, researchers from the Luikart Laboratory at Dartmouth University’s Geisel School of Medicine and the Weston Laboratory at the University of Vermont analyzed the impact of PTEN mutations in mice. The researchers discovered a significant increase in synaptic connections between neurons, which might explain ASD symptoms.

"In recent years, researchers have established a strong association between certain mutated genes and ASD," the Geisel School of Medicine states in a press release about the study. "One of the most common is called PTEN, which normally functions to control cell growth and regulate the ability of neurons to alter the strength of their connections. When mutated, PTEN is a cause of not only ASD, but also macrocephaly (enlarged head) and epilepsy."

Bryan Luikart, Ph.D, an associate professor of molecular and systems biology at Dartmouth's Geisel School of Medicine, explained the significance of PTEN mutations in previous studies.

 "Our lab and many others have shown that PTEN mutations result in an increase in the number of excitatory synaptic connections between neurons in mice - which we believe could be the fundamental basis for the symptoms exhibited by ASD patients," Luikart said in the press release.

To mimic the genetic defects found in human autism patients, the researchers engineered viruses to "knock out" the normal PTEN gene in mice and replaced it with the mutated human PTEN gene. This enabled them to study how neuronal function was altered in the mice using advanced imaging and electrophysiological techniques.

"Essentially, what we've found is that the mutated PTEN gene causes neurons to grow at twice the size of a normal neuron and forms about four times the number of synaptic connections with other neurons," Luikart said in the release. 

Building on this foundational discovery, the research team aimed to explore the role of other genes and signaling pathways in normal PTEN loss. Their investigations led them to the Raptor gene, an essential component of the mTORC1 signaling pathway. 

"We were able to determine that taking out the Raptor gene rescued all of the neuronal overgrowth and synapses that occur with normal PTEN loss," Luikart said in the release. "Additionally, by using the drug Rapamycin to inhibit the mTORC1 pathway, which is crucial for neuronal growth and synapse formation, we found that it rescued all of the changes in neuronal overgrowth." 

Earlier this year, Rapamycin was administered to children with ASD in a clinical trial, with some benefit to their symptoms. However, Luikart stated that in order to achieve optimal therapeutic effects, it is important to target genetic changes associated with ASD before the onset of symptoms.

"If we find that treating with a drug like Rapamycin early enough fixes the actual behavior problems of autism in a human patient, then that tells us we're really on to something," Luikart said in the release, "that these changes that we're seeing and fixing in our model organism are the cellular or physiological basis of autism in humans."

The study's insights into the neurobiological mechanisms behind ASD provide a promising step forward in understanding the disorder and developing effective treatments. As researchers continue to unravel the complexities of autism spectrum disorders, these findings offer hope for a better future for individuals and families affected by this condition. 

The collaborative efforts of the Luikart Laboratory at Dartmouth's Geisel School of Medicine and the Weston Laboratory at the University of Vermont have paved the way for transformative research in the field of neurobiology and autism spectrum disorders. As scientists worldwide work together to harness these discoveries, there is optimism that targeted interventions like Rapamycin could offer new avenues of hope and healing for those living with ASD.