Bolliger MF

References (5)

Title : Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior - Blundell_2010_J.Neurosci_30_2115
Author(s) : Blundell J , Blaiss CA , Etherton MR , Espinosa F , Tabuchi K , Walz C , Bolliger MF , Sudhof TC , Powell CM
Ref : Journal of Neuroscience , 30 :2115 , 2010
Abstract : Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist d-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
ESTHER : Blundell_2010_J.Neurosci_30_2115
PubMedSearch : Blundell_2010_J.Neurosci_30_2115
PubMedID: 20147539

Title : A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export - Zhang_2009_J.Neurosci_29_10843
Author(s) : Zhang C , Milunsky JM , Newton S , Ko J , Zhao G , Maher TA , Tager-Flusberg H , Bolliger MF , Carter AS , Boucard AA , Powell CM , Sudhof TC
Ref : Journal of Neuroscience , 29 :10843 , 2009
Abstract : Neuroligins (NLs) are postsynaptic cell-adhesion molecules essential for normal synapse function. Mutations in neuroligin-4 (NL4) (gene symbol: NLGN4) have been reported in some patients with autism spectrum disorder (ASD) and other neurodevelopmental impairments. However, the low frequency of NL4 mutations and the limited information about the affected patients and the functional consequences of their mutations cast doubt on the causal role of NL4 mutations in these disorders. Here, we describe two brothers with classical ASD who carry a single amino-acid substitution in NL4 (R87W). This substitution was absent from the brothers' asymptomatic parents, suggesting that it arose in the maternal germ line. R87 is conserved in all NL isoforms, and the R87W substitution is not observed in control individuals. At the protein level, the R87W substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells, destabilized NL4, caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons, and blocked NL4 transport to the cell surface. As a result, the R87W substitution inactivated the synapse-formation activity of NL4 and abolished the functional effect of NL4 on synapse strength. Viewed together, these observations suggest that a point mutation in NL4 can cause ASD by a loss-of-function mechanism.
ESTHER : Zhang_2009_J.Neurosci_29_10843
PubMedSearch : Zhang_2009_J.Neurosci_29_10843
PubMedID: 19726642

Title : Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2 - Blundell_2009_Genes.Brain.Behav_8_114
Author(s) : Blundell J , Tabuchi K , Bolliger MF , Blaiss CA , Brose N , Liu X , Sudhof TC , Powell CM
Ref : Genes Brain Behav , 8 :114 , 2009
Abstract : Neuroligins (NL) are postsynaptic cell adhesion molecules that are thought to specify synapse properties. Previous studies showed that mutant mice carrying an autism-associated point mutation in NL3 exhibit social interaction deficits, enhanced inhibitory synaptic function and increased staining of inhibitory synaptic puncta without changes in overall inhibitory synapse numbers. In contrast, mutant mice lacking NL2 displayed decreased inhibitory synaptic function. These studies raised two relevant questions. First, does NL2 deletion impair inhibitory synaptic function by altering the number of inhibitory synapses, or by changing their efficacy? Second, does this effect of NL2 deletion on inhibition produce behavioral changes? We now show that although NL2-deficient mice exhibit an apparent decrease in number of inhibitory synaptic puncta, the number of symmetric synapses as determined by electron microscopy is unaltered, suggesting that NL2 deletion impairs the function of inhibitory synapses without decreasing their numbers. This decrease in inhibitory synaptic function in NL2-deficient mice correlates with a discrete behavioral phenotype that includes a marked increase in anxiety-like behavior, a decrease in pain sensitivity and a slight decrease in motor co-ordination. This work confirms that NL2 modulates inhibitory synaptic function and is the first demonstration that global deletion of NL2 can lead to a selective behavioral phenotype.
ESTHER : Blundell_2009_Genes.Brain.Behav_8_114
PubMedSearch : Blundell_2009_Genes.Brain.Behav_8_114
PubMedID: 19016888

Title : Unusually rapid evolution of Neuroligin-4 in mice - Bolliger_2008_Proc.Natl.Acad.Sci.U.S.A_105_6421
Author(s) : Bolliger MF , Pei J , Maxeiner S , Boucard AA , Grishin NV , Sudhof TC
Ref : Proc Natl Acad Sci U S A , 105 :6421 , 2008
Abstract : Neuroligins (NLs) are postsynaptic cell-adhesion molecules that are implicated in humans in autism spectrum disorders because the genes encoding NL3 and NL4 are mutated in rare cases of familial autism. NLs are highly conserved evolutionarily, except that no NL4 was detected in the currently available mouse genome sequence assemblies. We now demonstrate that mice express a distant NL4 variant that rapidly evolved from other mammalian NL4 genes and that exhibits sequence variations even between different mouse strains. Despite its divergence, mouse NL4 binds neurexins and is transported into dendritic spines, suggesting that the core properties of NLs are retained in this divergent NL isoform. The selectively rapid evolution of NL4 in mice suggests that its function in the brain is under less stringent control than that of other NLs, shedding light on why its mutation in autism spectrum disorder patients is not lethal, but instead leads to a discrete developmental brain disorder.
ESTHER : Bolliger_2008_Proc.Natl.Acad.Sci.U.S.A_105_6421
PubMedSearch : Bolliger_2008_Proc.Natl.Acad.Sci.U.S.A_105_6421
PubMedID: 18434543
Gene_locus related to this paper: mouse-4neur

Title : Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression - Bolliger_2001_Biochem.J_356_581
Author(s) : Bolliger MF , Frei K , Winterhalter KH , Gloor SM
Ref : Biochemical Journal , 356 :581 , 2001
Abstract : Neuroligins, first discovered in rat brain, form a family of three synaptically enriched membrane proteins. Using reverse transcription-PCR of human brain polyadenylated RNA and extensive database searches, we identified the human homologues of the three rat neuroligins and a cDNA encoding a fourth member, which we named neuroligin 4. Neuroligin 4 has 63-73% amino acid identity with the other members of the human neuroligin family, and the same predicted domain structure. DNA database analyses, furthermore, indicated that a possible fifth neuroligin gene may be present in the human genome. Northern-blot analysis revealed expression of neuroligin 4 in heart, liver, skeletal muscle and pancreas, but barely at all in brain. Overexpression of neuroligin 4 cDNA in COS-7 cells led to the production of a 110 kDa protein. Immunofluorescence analysis demonstrated that the protein was integrated into the plasma membrane. Overexpression of cDNAs encoding neuroligin 4 and the PDZ-domain protein, PSD-95, in COS-7 cells resulted in the formation of detergent-resistant complexes. Neuroligin 4 did not bind to ZO-1, another PDZ-domain protein. Together, our data show that the human neuroligin family is composed of at least one additional member, and suggest that neuroligin 4 may also be produced outside the central nervous system.
ESTHER : Bolliger_2001_Biochem.J_356_581
PubMedSearch : Bolliger_2001_Biochem.J_356_581
PubMedID: 11368788
Gene_locus related to this paper: human-NLGN4X