Nlgn2, or Neuroligin-2, is a key synaptic adhesion protein predominantly found at GABAergic synapses. It is crucial for recruiting GABAARs by facilitating the assembly of the postsynaptic gephyrin scaffold, thus playing a vital role in inhibitory synaptic transmission [1]. Genetic models, such as KO mouse models, are valuable for studying Nlgn2's functions.

In Nlgn2 knockout mice, there are abnormal cytosolic gephyrin aggregation, reduced inhibitory synaptic transmission, and exacerbated anxiety-related behavior [1]. In schizophrenia, iPSC-derived cortical interneurons from patients show reduced levels of NLGN2, along with synaptic deficits. Overexpression of NLGN2 in these neurons rescues synaptic puncta deficits, while knockdown in healthy neurons leads to reduced synaptic puncta density [2]. In the context of pancreatic intraepithelial neoplasia, NLGN2 expressed by pancreatic exocrine cells is involved in regulating contact inhibition and epithelial polarity, with its loss associated with the progression from low-to high-grade lesions [3].

In summary, Nlgn2 is essential for proper inhibitory synaptic function at GABAergic synapses. Studies using gene knockout models have revealed its significant roles in mental health-related conditions like schizophrenia and anxiety, as well as in pancreatic tumor progression. Understanding Nlgn2 through these models provides insights into the underlying mechanisms of these diseases, potentially guiding the development of new therapeutic strategies.

References:

1. Zeppillo, Tommaso, Ali, Heba, Ravichandran, Sowbarnika, Taschenberger, Holger, Krueger-Burg, Dilja. 2024. Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation. In Communications biology, 7, 1157. doi:10.1038/s42003-024-06789-z. https://pubmed.ncbi.nlm.nih.gov/39284869/

2. Kathuria, Annie, Lopez-Lengowski, Kara, Watmuff, Bradley, Cohen, Bruce M, Karmacharya, Rakesh. 2019. Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine. In Translational psychiatry, 9, 321. doi:10.1038/s41398-019-0660-x. https://pubmed.ncbi.nlm.nih.gov/31780643/

3. Middonti, Emanuele, Astanina, Elena, Vallariello, Edoardo, Arese, Marco, Bussolino, Federico. 2024. A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia. In EMBO reports, 25, 1886-1908. doi:10.1038/s44319-024-00104-x. https://pubmed.ncbi.nlm.nih.gov/38413734/