Nlgn3, short for neuroligin-3, is a postsynaptic cell adhesion molecule. It is involved in synapse assembly and function at both excitatory and inhibitory synapses [2]. It has been associated with the pathophysiology of neurodevelopmental disorders as the Nlgn3 gene is located on the X chromosome [2]. Nlgn3 can form heterodimers with other Nlgns and is known to be regulated by cyclin-dependent kinase 5 (Cdk5), which phosphorylates Nlgn3 on serine 725, affecting its association with Kalirin-7 and its surface expression and synaptic currents [2].

In disease-related studies, patient-derived orthotopic xenografts of pediatric glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG) and adult GBM fail to grow in Nlgn3 knockout mice, indicating that high-grade glioma (HGG) growth depends on microenvironmental Nlgn3 [3]. Also, neuronal silencing of Nlgn3 in mice inhibits Akt activation and intensifies middle cerebral artery occlusion (MCAO)-induced ischemic brain injury, while neuronal overexpression of Nlgn3 increases Akt activation and alleviates such injury, suggesting Nlgn3 activates Gαi1/3-Akt signaling to protect neuronal cells from ischemia-reperfusion injury [1].

In conclusion, Nlgn3 is crucial for synapse-related functions. Gene knockout mouse models have revealed its significant roles in high-grade glioma growth and protection against ischemic brain injury. These findings contribute to understanding the underlying mechanisms of related diseases and may provide potential therapeutic targets.