Synaptic Deficits in Adnp-Mutant Mice Are Ameliorated by Histone Demethylase LSD1 Inhibition
Chih-Hung Lin
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorYong Ren
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorKin Wai Tam
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorMegan Conrow-Graham
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorCorresponding Author
Zhen Yan
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Correspondence:
Zhen Yan ([email protected])
Search for more papers by this authorChih-Hung Lin
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorYong Ren
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorKin Wai Tam
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorMegan Conrow-Graham
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorCorresponding Author
Zhen Yan
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
Correspondence:
Zhen Yan ([email protected])
Search for more papers by this authorFunding: This work was supported by National Institutes of Health (Grants NS127728 and MH126443).
ABSTRACT
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 (Adnpmut). We found that PFC pyramidal neurons in Adnpmut 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 Adnpmut mice. We found that treatment with an LSD1 inhibitor significantly elevated EPSC and IPSC in PFC pyramidal neurons of Adnpmut 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 Adnpmut 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.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.
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