Animals with a mutation in DYRK1A, an enzyme associated with neurodevelopmental disorders, presented microcephaly, synaptic and behavioral deficits, linked to alterations in brain signaling pathways. Early treatment with lithium reversed these deficits, restoring brain, social and synaptic functions. The results highlight the potential of lithium as a therapy for conditions such as ASD and intellectual disability, offering new perspectives for future treatments.
DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase 1A) is an enzyme belonging to the serine/threonine kinase group, which plays a crucial role in brain development.
Previous studies have linked it to Down syndrome, a genetic condition caused by trisomy of chromosome 21, where overexpression of DYRK1A is associated with learning and memory deficits and alterations in neuronal and synaptic development.
However, recent discoveries have expanded our understanding of DYRK1A, showing that its reduced, rather than increased, expression is linked to a range of neurodevelopmental brain disorders, such as developmental delay, microcephaly, autism spectrum disorder (ASD), intellectual disability and seizures.
Genetic studies have shown that mutations in DYRK1A occur in 0.1–0.5% of cases of ASD and/or intellectual disability and in up to 0.5% of developmental disorders. Therefore, animal models capable of reproducing these human conditions are essential to unravel the underlying mechanisms.
Researchers created mice carrying a specific DYRK1A mutation identified in human patients (Ile48LysfsX2, or Dyrk1a-I48K).
These mice exhibited a range of characteristics, including microcephaly (a reduction in brain size of up to 25% in certain regions), shorter dendrites, less functional excitatory synapses, and social impairments.
A Dyrk1a+/- mouse and a WT littermate at 12 weeks of age. Brains of a control and mutant at 12 weeks of age. Source: Cortes et al. https://doi.org/10.1101/2022.01.21.477242
The proteomic analyses performed in this study identified significant changes in proteins associated with several brain signaling pathways that play fundamental roles in the development and functioning of the nervous system.
Among these pathways, the insulin pathway stands out for regulating neuronal growth, synaptic plasticity, and energy metabolism in the brain.
The cAMP (cyclic adenosine monophosphate) pathway, in turn, is essential for communication between neurons and for the formation of memory and learning. Oxytocin, often called the "bonding hormone," is involved in the modulation of social and emotional behaviors.
AMPK (AMP-activated protein kinase) regulates cellular energy and the response to metabolic stress, while autophagy is a crucial process for cell cleansing and renewal, ensuring the health of neural structures.
Alterations in these pathways can result in deficits in brain development and neuronal function, as observed in the mutant mice studied, reinforcing the importance of correcting these imbalances to restore functional normality in the brain.
Heat maps showing volumetric changes (large reductions) in various brain regions of Dyrk1a-KI mice (8 weeks, male) compared to WT mice, as assessed by MRI.
Researchers at the Institute for Basic Science (IBS), Daejeon, Korea, have made a striking discovery. They performed early and chronic lithium treatment, starting soon after birth in the mutant mice, successfully reversed many of the deficits observed. The effects of lithium included rescuing:
Brain size and synaptic density.
Dendritic morphology, which is essential for neuronal communication.
Social and behavioral skills, resulting in long-lasting improvements in the mice’s lifespan.
Researchers believe that lithium works by correcting alterations in signaling pathways, such as those related to insulin, AMPK, and gap junctions.
These pathways are known to regulate dendritic arborization, which is essential for establishing healthy neural networks.
Early lithium treatment in Dyrk1a-KI mice rescues dendritic branching and synaptic transmission. Pups were given lithium carbonate via maternal milk until weaning on day 21 (~P21), followed by Sholl analysis, mEPSC recording, and synaptic density studies. After 28 days of birth (~P28), mice were evaluated for behavior and communication. Lithium normalized dendritic arborization in pyramidal neurons of the hippocampus and mPFC, as per Sholl analysis.
The results of this study complement previous findings in animal models and humans. For example, similar mutations in DYRK1A have previously been associated with deficits in cortical neuron growth and synaptic density.
The novelty here is to show how a specific mutation, identified in humans, affects multiple cell types in the brain and how these effects can be reversed with therapeutic intervention.
Lithium, traditionally used as the gold standard in the treatment of bipolar disorder, has shown promising results in animal models of ASD and other neurodevelopmental conditions.
This study reinforces the therapeutic potential of lithium to treat deficiencies caused by mutations in DYRK1A, by restoring critical signaling pathways and brain functions.
In addition, the pathways rescued by lithium, such as those related to insulin, oxytocin and AMPK, are critical not only for brain development, but also for the prevention of disorders related to neuroplasticity and synaptic communication.
With further research, these findings may be applied to human treatments, bringing hope to people affected by ASD and related conditions.
READ MORE:
Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice
Junyeop Daniel Roh, Mihyun Bae, Hyosang Kim, Yeji Yang, Yeunkeum Lee, Yisul Cho, Suho Lee, Yan Li, Esther Yang, Hyunjee Jang, Hyeonji Kim, Hyun Kim, Hyojin Kang, Jacob Ellegood, Jason P. Lerch, Yong Chul Bae, Jin Young Kim, and Eunjoon Kim
Mol Psychiatry (2024).
Abstract:
Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.
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