LRRC7 regulates neurite morphogenesis through mGluR5

Abstract

LRRC7 (Leucine-rich repeat containing 7) encodes for Densin-180, a scaffold protein in the postsynaptic density. LRRC7 has been reported as a risk allele for childhood emotional dysregulation and autism spectrum disorder. Knockout mice were reported to have defects related to metal illnesses and abnormal dendritic spine development. To further define the role of LRRC7 in behavioural control, we made use of our transgenic mice line carrying a hypomorphic allele of Lrrc7. Mutant mice exhibited features of childhood emotional dysregulation, including excessive following and fighting at juvenile stage. Behavioural tests in young adults confirmed increased anxiety, abnormal social behavior and defective spatial working memory in mutants. To reveal the molecular defects, we examined the dendritic complexity of hippocampal neurons in adult brain and in primary neurons from embryos. Mutant mice showed reduced dendritic complexity in both cases. Using primary neurons, we demonstrated that there was a reduced surface localization of mGlu5 receptor. Furthermore, augmentation of mGlu5 with CDPPB rescued the defects of neurite growth. To test for therapeutic potential of augmenting mGlu5 signaling in developmental emotional dysregulation, we tried acute injection of CDPPB and found that the treatment could alleviate the anxiety-like behavior and excessive social interaction of mutant mice. Our data suggested that Lrrc7 mutant mice provide a valuable model for developmental emotional dysregulation and identify a novel role of LRRC7 as a scaffold for the regulation of mGlu5 trafficking and activity. Our data also highlight a novel role of mGlu5 signaling in early neuron morphogenesis.