New research provides new insights into genetic mutations in autism and points to possible treatments

The findings of a new study published in Cell Reports, involving a collaboration between researchers in Luikart's lab at Dartmouth's Geisel School of Medicine and the University of Vermont's Weston Laboratory, provide further insights into the neurobiological basis of autism spectrum disorder (ASD) and point to possible treatments
.

In recent years, researchers have established a strong link
between certain mutated genes and autism spectrum disorder.
One of the most common is called PTEN, which usually controls cell growth and regulates the ability of neurons to change the strength of
connections.
When PTEN is mutated, it causes not only ASD, but also macrocephaly (enlarged head) and epilepsy
.

"In previous studies, our lab and many others have shown that PTEN mutations lead to an increase in the number of excitatory synaptic connections between neurons in mice—we believe this may be the basic basis for the symptoms exhibited by ASD patients," explains Bryan Luikart, Ph.
D.

, associate professor of molecular and systems biology at the Geisel School of Medicine at Dartmouth.

To mimic the genetic defects found in humans with autism, Luikart and his colleagues engineered the virus to "knock out" the PTEN gene in normal mice and replace it
with a mutated human PTEN gene.
They then used sophisticated imaging and electrophysiological techniques to study how neuronal function changed in
mice.

"Essentially, we've found that it causes neurons to grow to twice the size of normal neurons, forming four times
as many synaptic connections with other neurons in the process than normal neurons," Luikart said.
He noted that this work is the basis of the new study, in which the team seeks to learn more about the role
of other genes and signaling pathways in the loss of normal PTEN.

"We were able to determine that if you took out a gene called Raptor, which is an important gene in the mTORC1 signaling pathway, it could save all neuronal overgrowth and synapses
that occur due to the loss of normal PTEN," he said.
"We also found that by using the drug rapamycin to inhibit the mTORC1 pathway—which is required for neuronal growth and synapse formation—it rescued all changes in
neuronal overgrowth.
"

In a clinical trial earlier this year, rapamycin, when given to children, showed some benefits
for autism symptoms.
"It's important to note that our work shows that in order to have the best chance of producing a therapeutic effect, these genetic changes associated with autism spectrum disorder really have to be targeted before
symptoms appear.
"

Nevertheless, the findings of this study have important implications
for better understanding the neural basis of autism spectrum disorder and developing effective treatments for patients.

"If we find that early drug treatments with drugs like rapamycin can solve the actual behavioral problems of people with autism in humans, then that tells us that we really found something — that these changes that we see and fix in model organisms are the cellular or physiological basis
of autism in humans," Luikart said.