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Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. | LitMetric

AI Article Synopsis

  • Cognitive deficits in Down syndrome (DS) are associated with increased synaptic inhibition, disrupting the balance of excitation and inhibition (E/I) in the brain.
  • The gene DYRK1A, found on chromosome 21, has been identified in mouse models as a potential contributor to these cognitive dysfunctions through alterations in its dosage and expression.
  • Overexpression of DYRK1A leads to changes in synaptic plasticity and increased GABAergic signaling, suggesting that targeting DYRK1A could be a therapeutic strategy for DS and possibly other psychiatric conditions characterized by similar E/I imbalances.

Article Abstract

Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations.

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http://dx.doi.org/10.1016/j.nbd.2014.04.016DOI Listing

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