Genetic mutations in autism provide new insights and point to possible treatments

The findings of a new study published in Cell Reports, involving a collaboration between researchers in the Luikart lab at Dartmouth's Geisel School of Medicine and the Weston lab at the University of Vermont, provide further insight 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 people with autism spectrum disorder," explains
Bryan Luikart, Ph.
D.
, associate professor of molecular and systems biology at Dartmouth's Geisel School of Medicine.

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 was altered 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 would save all the neuronal overgrowth and synapses
that occur due to the loss of normal PTEN," he said.
We also found that by using the rapamycin drug to inhibit the mTORC1 pathway—which is required for neuronal growth and synapse formation—it salvaged 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 drugs like rapamycin can address the actual behavioral problems of autism in humans early enough, then that tells us that we have 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.

Kamran Tariq, Erin Cullen, Stephanie A.
Getz, Andie K.
S.
Conching, Andrew R.
Goyette, Mackenzi L.
Prina, Wei Wang, Meijie Li, Matthew C.
Weston, Bryan W.
Luikart.
Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss.
Cell Reports, 2022; 41 (5): 111574