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

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.