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<p>Haploinsufficiency of <i>Dyrk1a</i>, which encodes the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), has been causally linked to autism. Here we examined transcriptomic, electrophysiological and behavioral alterations in mice carrying a loss-of-function mutation of <i>Dyrk1a</i> (<i>Dyrk</i><sup>mut</sup>). We found that genes downregulated in prefrontal cortex (PFC) of male and female <i>Dyrk</i><sup>mut</sup> mice were enriched in chemical synaptic transmission and trans-synaptic signaling. In PFC pyramidal neurons of <i>Dyrk</i><sup>mut</sup> mice, the frequency of synaptic-driven spontaneous action potentials (sAP) was significantly reduced, and glutamatergic excitatory postsynaptic currents (EPSC) and GABAergic inhibitory postsynaptic currents (IPSC) were markedly diminished. Furthermore, autism-like social preference deficits and elevated anxiety were manifested in <i>Dyrk</i><sup>mut</sup> mice of both sexes. A short treatment of <i>Dyrk</i><sup>mut</sup> mice with an inhibitor of the epigenetic corepressor lysine-specific histone demethylase 1A (LSD1) led to a significant elevation of sAP frequency, EPSC and IPSC in PFC pyramidal neurons of <i>Dyrk</i><sup>mut</sup> mice. Moreover, the LSD1 inhibitor ameliorated social deficits in <i>Dyrk</i><sup>mut</sup> mice and reduced anxiety in <i>Dyrk</i><sup>mut</sup> males. Therefore, these data have not only revealed synaptic and behavioral deficits in PFC induced by <i>Dyrk1a</i> mutation, but also uncovered the therapeutic potential of LSD1 inhibition in <i>Dyrk1a</i>-deficient conditions.</p>

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Epigenetic treatment of synaptic and behavioral deficits in Dyrk1a-mutant mice

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  • 发表日期：

    2026年1月20日

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  • Chih-Hung Lin,
  • Mingjun Yu,
  • Prachetas Jai Patel,
  • Pei Li,
  • Zhen Yan

摘要

Haploinsufficiency of Dyrk1a, which encodes the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), has been causally linked to autism. Here we examined transcriptomic, electrophysiological and behavioral alterations in mice carrying a loss-of-function mutation of Dyrk1a (Dyrkmut). We found that genes downregulated in prefrontal cortex (PFC) of male and female Dyrkmut mice were enriched in chemical synaptic transmission and trans-synaptic signaling. In PFC pyramidal neurons of Dyrkmut mice, the frequency of synaptic-driven spontaneous action potentials (sAP) was significantly reduced, and glutamatergic excitatory postsynaptic currents (EPSC) and GABAergic inhibitory postsynaptic currents (IPSC) were markedly diminished. Furthermore, autism-like social preference deficits and elevated anxiety were manifested in Dyrkmut mice of both sexes. A short treatment of Dyrkmut mice with an inhibitor of the epigenetic corepressor lysine-specific histone demethylase 1A (LSD1) led to a significant elevation of sAP frequency, EPSC and IPSC in PFC pyramidal neurons of Dyrkmut mice. Moreover, the LSD1 inhibitor ameliorated social deficits in Dyrkmut mice and reduced anxiety in Dyrkmut males. Therefore, these data have not only revealed synaptic and behavioral deficits in PFC induced by Dyrk1a mutation, but also uncovered the therapeutic potential of LSD1 inhibition in Dyrk1a-deficient conditions.