Lithium, a drug commonly used to treat bipolar disorder and depression, has emerged as a potential therapy for autism spectrum disorder (ASD), according to a groundbreaking study.
Researchers at the Center for Synaptic Brain Dysfunctions, led by Director Kim Eunjoon at the Institute for Basic Science (IBS), discovered that lithium could restore brain function and improve behaviors in animal models of ASD caused by mutations in the Dyrk1a gene.
ASD is a neurodevelopmental condition that affects approximately 2.8% of the global population. It is characterized by challenges in social interaction, repetitive behaviors, intellectual difficulties, and anxiety.
Despite its prevalence, there are no definitive treatments for the core symptoms of ASD, leaving families and society grappling with the heavy burden of care. The urgent need for effective therapies has driven researchers to explore new approaches.
Among the many genetic factors linked to ASD, mutations in the Dyrk1a gene are particularly significant. These mutations lead to Dyrk1a syndrome, a condition associated with ASD, microcephaly (abnormally small brain size), language difficulties, social challenges, and anxiety.
To better understand how Dyrk1a mutations contribute to ASD symptoms, the researchers created a mouse model carrying a mutation that mimics human Dyrk1a-related conditions.
The study revealed that Dyrk1a mutations disrupt a key cellular pathway involving mTOR (mammalian target of rapamycin), which plays a crucial role in brain development and function.
However, generating live mice with the complete loss of Dyrk1a expression proved extremely challenging, as this condition is typically lethal during embryonic development.
By modifying the genetic background of the mice, the team was able to produce a small number of live mutant mice for further investigation.
The results of the study were striking. The researchers found that the phosphorylation (a chemical process critical for cellular signaling) of mTOR and related components was altered in mice with Dyrk1a mutations.
This disruption was linked to severe brain abnormalities, including microcephaly, and behavioral symptoms resembling those seen in individuals with ASD.
To address these deficits, the researchers turned to lithium as a potential treatment. When administered to the mutant mice during their juvenile period, lithium produced remarkable results.
It normalized brain size, repaired the structure and function of excitatory neurons (essential for communication between brain cells), and significantly improved behaviors related to anxiety and social interaction.
Even more impressively, these benefits persisted into adulthood, suggesting that lithium could offer lasting improvements by enabling structural and functional recovery in the brain.
Through advanced protein analysis, the team identified Kalirin-7, a molecule critical for maintaining healthy synapses (the connections between neurons), as a key target of lithium’s therapeutic effects. By stabilizing Kalirin-7 and restoring balance in the brain’s signaling networks, lithium addressed one of the core mechanisms underlying ASD symptoms.
“This is an exciting breakthrough,” said Dr. Roh Junyeop, a senior researcher and co-author of the study. “Dyrk1a mutations disrupt neural connectivity, much like traffic jams blocking roads in a city. Lithium clears the congestion, allowing smooth communication between neurons again.”
Director Kim Eunjoon emphasized the significance of these findings, noting, “Our research shows that lithium, a well-established drug for bipolar disorder, could also be an effective treatment for ASD.
The fact that its effects last long after treatment ends highlights the importance of early intervention during critical developmental periods.”
Published in Molecular Psychiatry on December 5, this research opens new doors for developing targeted therapies for ASD. By addressing the root causes of brain dysfunction, it offers hope for reducing the challenges faced by individuals and families affected by ASD.
It also underscores the critical importance of early diagnosis and intervention, potentially transforming the outlook for those living with this complex disorder.
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The research findings can be found in Molecular Psychiatry.
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