PRMT7 deficiency causes dysregulation of the HCN channels in the CA1 pyramidal cells and impairment of social behaviors

Abstract

HCN channels regulate excitability and rhythmicity in the hippocampal CA1 pyramidal cells. Perturbation in the HCN channel current (I h ) is associated with neuropsychiatric disorders, such as autism spectrum disorders. Recently, protein arginine methyltransferase 7 (PRMT7) was shown to be highly expressed in the hippocampus, including the CA1 region. However, the physiological function of PRMT7 in the CA1 neurons and the relationship to psychiatric disorders are unclear. Here we showed that PRMT7 knockout (KO) mice exhibit hyperactivity and deficits in social interaction. The firing frequency of the CA1 neurons in the PRMT7 KO mice was significantly higher than that in the wild-type (WT) mice. Compared with the WT CA1 neurons, the PRMT7 KO CA1 neurons showed a more hyperpolarized resting potential and a higher input resistance, which were occluded by the I h -current inhibitor ZD7288; these findings were consistent with the decreased I h and suggested the contribution of I h -channel dysfunction to the PRMT7 KO phenotypes. The HCN1 protein level was decreased in the CA1 region of the PRMT7 KO mice in conjunction with a decrease in the expression of Shank3, which encodes a core scaffolding protein for HCN channel proteins. A brief application of the PRMT7 inhibitor DS437 did not reproduce the phenotype of the PRMT7 KO neurons, further indicating that PRMT7 regulates I h by controlling the channel number rather than the open probability. Moreover, shRNA-mediated PRMT7 suppression reduced both the mRNA and protein levels of SHANK3, implying that PRMT7 deficiency might be responsible for the decrease in the HCN protein levels by altering Shank3 expression. These findings reveal a key role for PRMT7 in the regulation of HCN channel density in the CA1 pyramidal cells that may be amenable to pharmacological intervention for neuropsychiatric disorders.

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

“…Furthermore, PRMT7 is involved in stress response and its inhibition significantly reduced levels of Heat Shock Protein 70 (HSP70) stress-associated proteins [ 82 ]. Discoveries regarding PRMT7 and the nervous system have been reported recently, with PRMT7 shown to be highly expressed in the hippocampus [ 83 ]. Lee et al have shown that PRMT7 regulates HCN channels in CA1 hippocampal pyramidal cells, which could have implications for neuropsychiatric disorders [ 83 ].…”

“…Discoveries regarding PRMT7 and the nervous system have been reported recently, with PRMT7 shown to be highly expressed in the hippocampus [ 83 ]. Lee et al have shown that PRMT7 regulates HCN channels in CA1 hippocampal pyramidal cells, which could have implications for neuropsychiatric disorders [ 83 ]. Additionally, PRMT7 has been shown to interact with the Beta-catenin-C-Myc axis and promote the growth of renal cell carcinoma (RCC) [ 84 ].…”

Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with NaV1.9

“…The PRMT7 inhibitor DS-437 (GLPBIO, GC45927, Montclair, CA) was dissolved at 100 mM in DMSO and stored. The concentration of drug administered was 10 mM and 100 mM, 19,39 as obtained by diluting the stock solution (DMSO # 0.1%). DS-437 was incubated with the neurons for 1 hour before current-clamp recordings.…”

PRMT7: A Pivotal Arginine Methyltransferase in Stem Cells and Development

“…Muscles derived from PRMT7 −/− mice displayed decreased oxidative metabolism [ 67 ]. In addition, Lee and colleagues reported that PRMT7 −/− mice showed hyperactivity as well as social interaction defects [ 68 ]. These findings demonstrate that PRMT7 −/− mice have defects in bone and skeletal muscle mass, delayed or impaired neuronal development, increased adipogenesis, and possibly also reduced male fertility.…”

“…Further analysis showed that PRMT7 was highly expressed in the CA1 field of the hippocampus, and PRMT7 −/− mice displayed defects in social behaviors [ 78 ]. Recent studies further revealed that PRMT7 −/− CA1 neurons exhibited HCN (hyperpolarization-activated, cyclic-nucleotide-gated) channel current dysfunction, which might be attributed to the decreased HCN protein levels mediated by SHANK3 downregulation [ 68 , 79 ]. These findings provide insights into the role and the underlying mechanisms of PRMT7 functioning in neuronal development.…”