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

Abstract 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 ( Dyrk mut ). We found that genes downregulated in prefrontal cortex (PFC) of male and female Dyrk mut mice were enriched in chemical synaptic transmission and trans-synaptic signaling. In PFC pyramidal neurons of Dyrk mut 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 Dyrk mut mice of both sexes. A short treatment of Dyrk mut 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 Dyrk mut mice. Moreover, the LSD1 inhibitor ameliorated social deficits in Dyrk mut mice and reduced anxiety in Dyrk mut 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.