Synaptic Deficits in <i>Adnp‐</i>Mutant Mice Are Ameliorated by Histone Demethylase <scp>LSD1</scp> Inhibition

ADNP (Activity-dependent neuroprotective protein) is a top-ranking autism risk gene. Here we examined synaptic alterations in heterozygous mice carrying an autism mutation on Adnp C-terminus (Adnp^mut). We found that PFC pyramidal neurons in Adnp^mut mice exhibited significantly diminished glutamatergic and GABAergic synaptic transmission, as indicated by markedly reduced excitatory postsynaptic currents (EPSC) and inhibitory postsynaptic currents (IPSC). Given the key role of ADNP in chromatin regulation and the constitutive association of the ADNP complex with lysine-specific demethylase 1 (LSD1), we examined the therapeutic effects of LSD1 inhibition in Adnp^mut mice. We found that treatment with an LSD1 inhibitor significantly elevated EPSC and IPSC in PFC pyramidal neurons of Adnp^mut mice, and the rescuing effect was particularly prominent in females. Biochemical assays revealed increased H3K4me2 and decreased H3K9me2/3 by LSD1 inhibitor treatment in female Adnp^mut mice, which were correlated with the elevated expression of synaptic genes linked to glutamatergic and GABAergic transmission after the treatment. These data have revealed synaptic deficits in PFC induced by a loss-of-function mutation of Adnp and uncovered the therapeutic potential of LSD1 inhibition in ADNP-deficient conditions, especially for females.