Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD.
Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility.
The neurobiological bases of autism spectrum disorders: the R451C-neuroligin 3 mutation hampers the expression of long-term synaptic depression in the dorsal striatum.
Global or VTA DA neuron-specific loss of the ASD-associated synaptic adhesion molecule neuroligin 3 alters the behavioral response toward nonfamiliar conspecifics and the reinforcing properties of conspecific interaction.
The Neuroligin-3 (NL3)<sup>R451C</sup> mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown.
Our results directly link Wnt/β-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.
Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients.
The Neuroligin-3 (NL3) mouse, expressing a R451C mutation discovered in two Swedish brothers with ASD, exhibits impaired social interactions and heightened aggressive behavior towards male mice.
Knock-in mice carrying a single rare point mutation of NLGN3 (NLGN3R451C) discovered in the patients with ASDs display a deficit in social interaction and an enhancement of spatial learning and memory ability reminiscent of the clinical phenotype of ASDs.
In the face of growing controversy about the utility of genetic mouse models of human disease, Rothwell et al. report on a shared mechanism by which two different neuroligin-3 mutations, associated with autism spectrum disorders in humans, produce an enhancement in motor learning.
FMRP, a protein with numerous proposed functions including regulation of mRNA and synaptic protein synthesis, and NLGN3, a member of the neuroligin synaptic cell-adhesion protein family, have been implicated in human ASD.
It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3.
The present study provides initial evidence that a common variant in NLGN3 gene may play a role in the etiology of ASDs among affected males in Chinese Han population, and further supports the hypothesis that defect of synapse might involvement in the pathophysiology of ASDs.
Both mutated CADM1 and neuroligin 3(R451C) induced upregulation of C/EBP-homologous protein (CHOP), an ER stress marker, suggesting that in addition to the trafficking impairment, this CHOP upregulation may also be involved in ASD pathogenesis.
We conclude that there is no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level in our study group.
Recent studies reported that sequence polymorphisms in neuroligin-3 (NLGN3) and neuroligin-4 (NLGN4) genes have been linked to autism spectrum disorders indicating neuroligin genes as candidate targets in brain disorders.
Neuroligin abnormalities have been recently implicated in the aetiology of autism spectrum disorders (ASD), given the finding of point mutations in the two X-linked genes NLGN3 and NLGN4X and the important role of neuroligins in synaptogenesis.
Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P=0.002), NLGN3 (DXS7132, P=0.014), and NLGN4 (DXS996, P=0.031).
A recent study reported that a mutation of neuroligin-3 (NL3), an X-linked gene, was found in siblings with autistic spectrum disorder in which two affected brothers had a point mutation that substituted a Cys for Arg451.