Neurexin-3 is primarily localized in the presynaptic membrane and forms complexes with various ligands located in the postsynaptic membrane. Neurexin-3 has important roles in synapse development and synapse functions. Neurexin-3 mediates excitatory presynaptic differentiation by interacting with leucine-rich-repeat transmembrane neuronal proteins. Meanwhile, neurexin-3 modulates the expression of presynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors and γ-aminobutyric acid A receptors by interacting with neuroligins at excitatory and inhibitory synapses. Numerous studies have documented the potential contribution of neurexin-3 to neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease, addiction behaviors, and other diseases, which raises hopes that understanding the mechanisms of neurexin-3 may hold the key to developing new strategies for related illnesses. This review comprehensively covers the literature to provide current knowledge of the structure, function, and clinical role of neurexin-3.

Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy–apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro, and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP.

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.