The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses

Krueger, Dilja D.; Tuffy, Liam P.; Papadopoulos, Theofilos; Brose, Nils

doi:10.1016/j.conb.2012.02.012

Cited by 216 publications

(194 citation statements)

References 82 publications

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…The synaptic proteins neurexins (Nrxns) and neuroligins (Nlgns) have emerged as a pair of fascinating candidates for underlying synaptic plasticity. Presynaptic Nrxns form transsynaptic complexes with postsynaptic Nlgns (Ushkaryov et al 1992;Yamagata et al 2003) and play an important role in differentiation, maturation, and stabilization of both excitatory and inhibitory synapses (Dean et al 2003;Graf et al 2004;Chubykin et al 2007;Budreck and Scheiffele 2007;Krueger et al 2012). These proteins not only facilitate the assembly of functional units on their own side of the synapses but also regulate synaptic specialization on the opposite side of a nascent synapse through their trans-synaptic interactions (Dean and Dresbach 2006).…”

Section: Introductionmentioning

confidence: 99%

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Kumar

Thakur

2015

AGE

View full text Add to dashboard Cite

Neurexin1 (Nrxn1) and Neuroligin3 (Nlgn3) are cell adhesion proteins, which play an important role in synaptic plasticity that declines with advancing age. However, the expression of these proteins during aging has not been analyzed. In the present study, we have examined the age-related changes in the expression of these proteins in cerebral cortex and hippocampus of 10-, 30-, 50-, and 80-week-old male mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis indicated that messenger RNA (mRNA) level of Nrxn1 and Nlgn3 significantly increased from 10 to 30 weeks and then decreased at 50 weeks in both the regions. However, in 80-week-old mice, Nrxn1 and Nlgn3 were further downregulated in cerebral cortex while Nrxn1 was downregulated and Nlgn3 was upregulated in hippocampus. These findings were corroborated by immunoblotting and immunofluorescence results. When the expression of Nrxn1 and Nlgn3 was correlated with presynaptic density marker synaptophysin, it was found that synaptophysin protein expression in cerebral cortex was high at 10 weeks and decreased gradually up to 80 weeks, whereas in hippocampus, it decreased until 50 weeks and then increased remarkably at 80 weeks. Furthermore, Pearson's correlation analysis showed that synaptophysin had a strong relation with Nrxn1 and Nlgn3 in cerebral cortex and with Nlgn3 in hippocampus. Thus, these findings showed that Nrxn1 and Nlgn3 are differentially expressed in cerebral cortex and hippocampus which might be responsible for alterations in synaptic plasticity during aging.

show abstract

Section: Introductionmentioning

confidence: 99%

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Kumar

Thakur

2015

AGE

View full text Add to dashboard Cite

show abstract

“…Neurexin-NL transsynaptic interactions constitute a key synaptic adhesion pathway that governs the formation, maturation, and plasticity of neuronal synapses (1,33). Recently, alternative trans-synaptic interaction proteins have been discovered for neurexins, including leucine-rich repeat transmembrane neuronal proteins (LRRTMs) and cerebellins/GluRδ2 (34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

139

View full text Add to dashboard Cite

The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

show abstract

“…In cultured neurons, overexpression of NL1 promotes clustering of synaptic NMDARs (8), and NL1 KO mice show decreases in NMDAR-dependent excitatory postsynaptic currents (NMDAR EPSCs) (9)(10)(11). A major question in understanding neuroligin function is how specific isoforms couple to specific neurotransmitter receptors (12,13). NMDARs were recovered in coimmunoprecipitations with NL proteins, indicating a potential complex formation, although in those experiments, no NL isoform-specificity was apparent (14).…”

mentioning

confidence: 99%

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Budreck

Kwon

Jung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

164

161

View full text Add to dashboard Cite

Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cisinteractions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.synapse | neurotranmitter receptor | neurexin N MDA receptors (NMDARs) are key regulators of the development of neural circuits and synaptic plasticity (1, 2). In humans, perturbation of NMDAR function results in psychotic conditions, and genetic animal models with altered NMDAR activity exhibit phenotypes related to cognitive disorders such as schizophrenia and autism (3-5). Activity-dependent recruitment of NMDARs to synapses controls certain forms of synaptic plasticity (6, 7). However, the molecular mechanisms underlying the recruitment and physical tethering of NMDAR complexes at synapses are incompletely understood.Neuroligin-1 (NL1), one of four postsynaptic neuroligin adhesion molecules (NL1, 2, 3, 4), contributes to NMDAR regulation (8, 9). In cultured neurons, overexpression of NL1 promotes clustering of synaptic NMDARs (8), and NL1 KO mice show decreases in NMDAR-dependent excitatory postsynaptic currents (NMDAR EPSCs) (9-11). A major question in understanding neuroligin function is how specific isoforms couple to specific neurotransmitter receptors (12, 13). NMDARs were recovered in coimmunoprecipitations with NL proteins, indicating a potential complex formation, although in those experiments, no NL isoform-specificity was apparent (14). One candidate link between NLs and glutamate receptors is through postsynaptic scaffolding molecules such as postsynaptic density 95 (PSD95) (15, 16). However, all NL isoforms contain PSD95 binding sites, and NMDARs and PSD95 were recruited to NL1 with different time courses (14).Our results demonstrate that NL1 controls synaptic abundance of NMDAR via NL1-specific extracellular determinants. Loss of these interactions results in impairment of NMDAR-mediated transmission and synaptic plasticity. Our findings uncover an unexpected mode of NL1-NMDAR coupling and demonstrate a key role for the NL1 adhesion protein in the physical incorporation and retention of NMDAR at glutamatergic synapses.Results NL1-Specific Recruitment of NMDARs Does Not Require PSD95. We examined the specificity of molecular coupling of NL isoforms (NL1, 2, 3) to NMDARs by NL overexpression in cultured hippocampal neurons. NL1 increased the density of clusters of the NMDAR subunits GluN1, GluN2A, and GluN...

show abstract

The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses

Cited by 216 publications

References 82 publications

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Contact Info

Product

Resources

About