A groundbreaking discovery has highlighted lithium—a drug long used to treat bipolar disorder and depression—as a potential therapy for autism spectrum disorder (ASD). This research, conducted by a team at the Center for Synaptic Brain Dysfunctions within the Institute for Basic Science (IBS) led by Director KIM Eunjoon, reveals that lithium can restore brain function and alleviate behavioral symptoms in animal models of ASD caused by mutations in the Dyrk1a gene.

ASD is a neurodevelopmental disorder affecting 2.8% of the global population, characterized by social deficits, repetitive behaviors, intellectual challenges, and anxiety. Because ASD imposes a heavy burden not only on the patients themselves but on their families and society as a whole, new therapeutic methods must be developed to treat the core symptoms of ASD. Despite its prevalence, there are no definitive treatments or preventive measures.

Among the many genetic risk factors for ASD, Dyrk1a mutations stand out as significant, leading to conditions such as Dyrk1a syndrome. Patients carrying Dyrk1a loss-of-function mutation have presented with ASD, microcephaly, language problems, social disability, and anxiety. The mouse model carrying Dyrk1a I48K truncation mutation (a human patient mutation), also mimics these phenotypes closely.

One of the underlying mechanisms of ASD symptoms by Dyrk1a mutation discovered within this study is impaired phosphorylation levels of mTOR (mammalian target of rapamycin). To find the specific substrate of Dyrk1a, the researchers needed to generate mice lacking the entirety of Dyrk1a expression (homozygote), a condition that has been known to be embryonically lethal. However, by switching the mouse genetic background, it was possible to generate live animals with this mutation. Even so, the survival rate was abysmal, with less than 5% of the mutant pups surviving. After overcoming this hardest part, the authors found that the phosphorylation levels of various elements of the mTOR pathway, and mTOR itself were altered by Dyrk1a expression levels.

Accordingly, they have chosen lithium to address this deficit, and as a tentative cure drug in Dyrk1a mutant mice. When lithium was administered to the mutant mice during their juvenile period, the results were remarkable. Lithium normalized brain size, restored the structure and function of excitatory neurons, and significantly improved behaviors related to anxiety and social interaction. Even more promising, the effects of this short-term treatment lasted into adulthood, suggesting that lithium may have long-term benefits by enabling structural and functional recovery in the brain.

Through advanced mass spectrometry analysis, proteins and their phosphorylation levels rescued by lithium in Dyrk1a mutation mice were extensively screened. The team discovered that lithium’s therapeutic effects are partly mediated through its action on Kalirin-7, a molecule essential for synaptic structure and function. By targeting this molecule, lithium helped to restore balance in the brain's signaling networks, addressing one of the core mechanisms of ASD.

“This is an exciting breakthrough,” said Dr. ROH Junyeop, a senior researcher and co-first author of the study. “Dyrk1a mutations disrupt neural connectivity, much like a traffic jam or roadblocks in a city. Lithium helps to clear the congestion, restoring smooth communication between neurons.”

Director KIM Eunjoon emphasized the potential impact of these findings, stating, “Our research shows that lithium, a widely used drug for bipolar disorder, could also serve as a treatment for ASD. The fact that its effects persist long after treatment ends underscores the importance of early intervention during critical developmental windows.”

This study, published in the prestigious journal Molecular Psychiatry on December 5, not only paves the way for new therapeutic approaches for ASD but also underscores the critical importance of early diagnosis and intervention. It offers a glimmer of hope to families and individuals affected by ASD, suggesting that targeted treatments may one day reduce the burden of this complex disorder.