NGL-1/LRRC4C-Mutant Mice Display Hyperactivity and Anxiolytic-Like Behavior Associated With Widespread Suppression of Neuronal Activity

Abstract

Netrin-G ligand-1 (NGL-1), encoded by Lrrc4c, is a post-synaptic adhesion molecule implicated in various brain disorders, including bipolar disorder, autism spectrum disorder, and developmental delay. Although previous studies have explored the roles of NGL-1 in the regulation of synapse development and function, the importance of NGL-1 for specific behaviors and the nature of related neural circuits in mice remain unclear. Here, we report that mice lacking NGL-1 (Lrrc4c–/–) show strong hyperactivity and anxiolytic-like behavior. They also display impaired spatial and working memory, but normal object-recognition memory and social interaction. c-Fos staining under baseline and anxiety-inducing conditions revealed suppressed baseline neuronal activity as well as limited neuronal activation in widespread brain regions, including the anterior cingulate cortex (ACC), motor cortex, endopiriform nucleus, bed nuclei of the stria terminalis, and dentate gyrus. Neurons in the ACC, motor cortex, and dentate gyrus exhibit distinct alterations in excitatory synaptic transmission and intrinsic neuronal excitability. These results suggest that NGL-1 is important for normal locomotor activity, anxiety-like behavior, and learning and memory, as well as synapse properties and excitability of neurons in widespread brain regions under baseline and anxiety-inducing conditions.

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

“…TRPS1 is a transcriptional repressor that binds to GATA-regulated genes during different stages of embryonic development to influence chondrocyte proliferation and differentiation (Wang et al, 2018). LRRC4C encodes a post-synaptic adhesion molecule that binds with the conserved family of netrin G ligand (NGL) proteins (Choi et al, 2019) to regulate synaptic organization. There is no previous evidence that TRPS1 and LRRC4C interact to influence schizophrenia; however, LRRC4C has been implicated in brain disorders including schizophrenia, bipolar disorder, autism spectrum disorder, and developmental delay (Maussion et al, 2017; Zhang et al, 2021).…”

“…Mouse models have shown that mice lacking NGL-1 exhibit hyperactivity and anxiolytic-like behavior due to widespread excitation of neurons in the brain. This suggests that LRRC4C plays a role in suppression or dampening of neuronal activity (Choi et al, 2019). We hypothesize that TRPS1 acts as a repressor of LRRC4C , which is supported by a previous analysis of GTEx bulk tissue expression data (GTEx Consortium, 2013) showing that LRRC4C (ENSG00000148948.7) is highly expressed in brain tissues, whereas TRPS1 (ENSG00000104447.12) is expressed at low levels in brain tissue compared with all other tissues.…”

Berberine Ameliorates Prenatal Dihydrotestosterone Exposure-Induced Autism-Like Behavior by Suppression of Androgen Receptor

“…The animal behavior test of offspring was carried out at 7-8 weeks of age. ALB was evaluated using ultrasonic vocalizations (Silverman et al, 2010;Schaafsma et al, 2017), social recognition tests (Moy et al, 2004;Schaafsma et al, 2017) and a three-chambered social test (Moy et al, 2004;Silverman et al, 2010;Schaafsma et al, 2017;Choi et al, 2019;Wang et al, 2019).…”

Education interacts with genetic variants near GJD2, RBFOX1, LAMA2, KCNQ5 and LRRC4C to confer susceptibility to myopia

“…NGL1 binds intracellularly with PSD-95, a postsynaptic scaffolding protein, and extracellularly with netrin-G1. This protein complex is thought to control the development of distinct populations of neuronal synapses and neural circuits [ 48 ]. Other LRRC4C variants are associated with developmental disorders such as autism [ 49 ].…”