title: Inhibition of coactivator-associated arginine methyltransferase 1 modulates dendritic arborization and spine maturation of cultured hippocampal neurons.
abstract: An improved understanding of the molecular mechanisms in synapse formation provides insight into both learning and memory and the etiology of neurodegenerative disorders. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein methyltransferase that negatively regulates synaptic gene expression and inhibits neuronal differentiation. Despite its regulatory function in neurons, little is known about the CARM1 cellular location and its role in dendritic maturation and synapse formation. Here, we examined the effects of CARM1 inhibition on dendritic spine and synapse morphology in the rat hippocampus. CARM1 was localized in hippocampal post-synapses, with immunocytochemistry and electron microscopy revealing co-localization of CARM1 with post-synaptic density (PSD)-95 protein, a post-synaptic marker. Specific siRNA-mediated suppression of CARM1 expression resulted in precocious dendritic maturation, with increased spine width and density at sites along dendrites and induction of mushroom-type spines. These changes were accompanied by a striking increase in the cluster size and number of key synaptic proteins, includingN-methyl-d-aspartate receptor subunit 2B (NR2B) and PSD-95. Similarly, pharmacological inhibition of CARM1 activity with the CARM1-specific inhibitor AMI-1 significantly increased spine width and mushroom-type spines and also increased the cluster size and number of NR2B and cluster size of PSD-95. These results suggest that CARM1 is a post-synaptic protein that plays roles in dendritic maturation and synaptic formation and that spatiotemporal regulation of CARM1 activity modulates neuronal connectivity and improves synaptic dysfunction.
authors.affiliation: From the Blanchette Rockefeller Neurosciences Institute, West Virginia University, Morgantown, West Virginia 26505 clim@hsc.wvu.edu.
authors.forename: Chol Seung
authors.initials: CS
authors.lastname: Lim
authors.affiliation: From the Blanchette Rockefeller Neurosciences Institute, West Virginia University, Morgantown, West Virginia 26505.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000201:enzymology*; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D057907:Post-Synaptic Density / Q000201:enzymology*; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1
keywords: CARM1; PSD; dendritic maturation; dendritic spine; hippocampal neurons; hippocampus; neuron; signal transduction; synapse; synaptic clustering