Neurexins and neuroligins are some of the best-characterized cell-adhesion molecules. They are trans-synaptic cell-adhesion molecules that mediate essential signaling between pre- and postsynaptic specializations, signaling that performs a central role in the brain’s ability to process information, and that is a key target in the pathogenesis of cognitive diseases (Südhof, 2008). And indeed, all human neurexin genes (NRXN1, NRXN2, NRXN3) and all (NLGN1, NGLN3, NLGN4X, NLGN4Y) but one human neuroligin gene (NLGN2) have been associated with autism. In addition, NRXN1 has also been associated with schizophrenia with high confidence (Kirov et al., 2009). Recent studies about neurexins and neuroligins are now making some inroads in two directions: 1) genotype-phenotype correlations, and 2) the basic science of how neurexins and neuroligins participate in the assembly of pre- and postsynaptic membranes, and how they mediate signaling between the two.

1. Schaaf et al. (Schaaf et al., 2012) reported on a cohort of 24 individuals with small NRXN1 deletions, and found that more C-terminal deletions, especially the ones encompassing the sequence encoding neurexin-1β, seem to predispose to both macrocephaly and epilepsy when compared to those only deleting N-terminal segments of the NRXN1 gene. Subsequently, Tanaka et al. (Tanaka et al., 2012) investigated the higher-order architecture of cell adhesion mediated by neurexin-1 and neuroligin-1, and found that the ectodomain complex of neurexin-1β and neuroligin-1 spontaneously assembles into crystals of a lateral, sheet-like superstructure topologically compatible with transcellular adhesion. However, this higher-order architecture was not formed between neuroligin-1 and the much longer neurexin-1α isoform, thereby suggesting a functional discrimination mechanism between synaptic contacts made by different isoforms of neurexin variants.

2. New studies that came out just last week provide intriguing insight into the underlying molecular mechanisms (Hu et al., 2012; Owald et al., 2012). Hu et al. show in C. elegans how neurexin and neuroligin mediate retrograde synaptic inhibition, with slow and prolonged postsynaptic responses in mutants of Nlg-1 or Nrx-1. In children with ASDs, it has been shown that acoustic responses are slower, and multisensory responses are integrated over a longer time window. In individuals with schizophrenia, abnormal sensory gating is a well-established phenomenon. The results of Hu’s study suggest that altered kinetics of synaptic responses could be an important cellular defect in ASDs and schizophrenia.

References:

Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature . 2008 Oct 16 ; 455(7215):903-11. Abstract

Schaaf CP, Boone PM, Sampath S, Williams C, Bader PI, Mueller JM, Shchelochkov OA, Brown CW, Crawford HP, Phalen JA, Tartaglia NR, Evans P, Campbell WM, Chun-Hui Tsai A, Parsley L, Grayson SW, Scheuerle A, Luzzi CD, Thomas SK, Eng PA, Kang SH, Patel A, Stankiewicz P, Cheung SW. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Eur J Hum Genet . 2012 May 23. Abstract

Kirov G, Rujescu D, Ingason A, Collier DA, O'Donovan MC, Owen MJ. Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull . 2009 Sep 1 ; 35(5):851-4. Abstract

Tanaka H, Miyazaki N, Matoba K, Nogi T, Iwasaki K, Takagi J. Higher-order architecture of cell adhesion mediated by polymorphic synaptic adhesion molecules neurexin and neuroligin. Cell Rep . 2012 Jul 26 ; 2(1):101-10. Abstract

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