Researchers to study molecular mechanisms behind susceptibility of males to autism

Chiara Manzini, PhD, received a grant to study the role of the CC2D1A gene in making males more susceptible to autism than females

Chiara Manzini, PhD, Assistant Professor of Pharmacology and Physiology at the GW School of Medicine and Health Sciences

Neurodevelopmental disorders such as autism spectrum disorder and intellectual disability are more prevalent in males than females. However, the underlying molecular mechanisms of why this difference occurs remain a mystery.

With more than $2 million from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, researchers at the George Washington University (GW) will study the CC2D1A gene and its role in the development of autism in males versus females. Chiara Manzini, PhD, assistant professor of pharmacology and physiology at the GW School of Medicine and Health Sciences and the GW Institute for Neuroscience, is leading the study into finding what makes male more susceptible to autism and intellectual disability.

"If there are fundamental differences that make males more susceptible to autism, this can be targeted by therapy development. It is possible that the drugs that we need to use for girls are different," explained Manzini, who has been researching this difference for the past five years. "This is a really big issue that the NIH has raised recently where a lot of studies or clinical trials were being done on males. When the same diseases were studied in females with the same drugs, the effect was different."

Based on previous research finding mutations in the CC2D1A gene, Manzini hypothesizes that the gene controls male-specific function of the cAMP response element binding (CREB) protein in the developing and adult hippocampus. The CREB protein can increase or decrease the expression of specific genes. As a result, the team believes that disrupted CREB function in males leads to altered plasticity and cognitive and affective phenotypes following loss of CC2D1A.

"We really hope to find this molecular switch that makes this deficit only present in boys to help us understand why girls are protected," said Manzini. "On the flip side, females are diagnosed more frequently with Alzheimer's. It's the opposite end of the human lifespan, but it's a cognitive disorder."

It's possible, she explained, that the same mechanisms that make males more susceptible to cognitive disorders earlier in life, make females susceptible later in life.

Manzini is collaborating with Peter Nemes, PhD, associate professor of chemistry and biochemistry at the University of Maryland, College Park and an expert in mass spectrometry. His expertise will help identify the proteins regulated by CC2D1A and CREB and help researchers understand the molecular differences between males and females when it comes to neurodevelopmental disorders.