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, including 
N-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.