Lithium Has Been Recently Identified As A Promising Therapy For Treating Autism
Lithium has traditionally been used to treat bipolar disorder and depression. However, researchers at the Center for Synaptic Brain Dysfunctions within the Institute for Basic Science (IBS) have recently identified this medication as a promising therapy for autism spectrum disorder (ASD).
Their study demonstrated that lithium may improve brain function and reduce behavioral symptoms in animal models of ASD linked to mutations in the Dyrk1a gene.
“This is an exciting breakthrough. Dyrk1a mutations disrupt neural connectivity, much like a traffic jam or roadblock in a city. Lithium helps to clear the congestion, restoring smooth communication between neurons,” explained Dr. Roh Junyeop, the study’s co-first author.
Approximately 2.8% of the global population is affected by ASD, a neurodevelopmental disorder marked by challenges in social interaction, repetitive behavior, intellectual difficulties, and anxiety. The impact of ASD extends beyond the individuals affected as well, placing a strain on families.
While ASD has widespread prevalence, effective treatments or preventive strategies for the core symptoms remain unavailable, highlighting an urgent need for new therapeutic approaches.
There are various genetic risk factors for ASD, but mutations in the Dyrk1a gene are particularly noticeable, as they can lead to Dyrk1a syndrome.
Individuals with Dyrk1a loss-of-function mutations often exhibit symptoms such as microcephaly, language impairments, social difficulties, and anxiety.
These traits are mirrored in a mouse model carrying the Dyrk1a I48K truncation mutation, a variation found in human patients, providing a valuable tool for studying the condition.
This study uncovered one of the mechanisms behind ASD symptoms associated with Dyrk1a mutations: disrupted phosphorylation of mTOR (mammalian target of rapamycin).
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To identify the specific substrate affected by Dyrk1a, the researchers attempted to create mice with no expression of Dyrk1a (homozygotes), a condition known to be lethal during embryonic development.
By altering the genetic background of the mice, they were able to successfully generate live animals with the mutation. However, the survival rate of mutant pups was extremely low, with fewer than 5% surviving.
Following this major hurdle, the researchers discovered that the expression levels of Dyrk1a affected the phosphorylation of several components in the mTOR pathway, including mTOR itself.
To address this deficiency, the team chose lithium as a potential treatment for Dyrk1a mutant mice. When administered during the juvenile phase, lithium produced striking results.
It normalized brain size, repaired the structure and function of excitatory neurons, and significantly improved anxiety and social interaction behaviors. Plus, the effects of this treatment, which is short-term, persisted into adulthood. This indicates that lithium could provide long-term benefits by supporting both structural and functional brain recovery.
Using advanced mass spectrometry analysis, the researchers extensively screened proteins and their phosphorylation levels restored by lithium in Dyrk1a mutant mice. They found that lithium’s therapeutic effects are partially driven by its impact on Kalirin-7, a molecule crucial for synaptic function and structure.
By targeting Kalirin-7, lithium helped rebalance the brain’s signaling networks and addressed one of the core mechanisms underlying ASD.
“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,” said Director Kim Eunjoon, who led the study.
To read the study’s complete findings, which have since been published in Molecular Psychiatry, visit the link here.
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