Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function

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Cell adhesion represents the most direct way of coordinating synaptic connectivity in the brain. Recent evidence highlights the importance of a trans-synaptic interaction between postsynaptic neuroligins and presynaptic neurexins. These transmembrane molecules bind each other extracellularly to promote adhesion between dendrites and axons. This signals the recruitment of presynaptic and postsynaptic molecules to form a functional synapse. Remarkably, neuroligins alone can induce the formation of fully functional presynaptic terminals in contacting axons. Conversely, neurexins alone can induce postsynaptic differentiation and clustering of receptors in dendrites. Therefore, the neuroligin–neurexin interaction has the unique ability to act as a bi-directional trigger of synapse formation. Here, we review several recent studies that offer clues as to how these proteins form synapses and how they might function in the brain to establish and modify neuronal network properties and cognition.

Introduction

Brain development and function rely on proper formation, maintenance and modification of connections between neurons. During development, axons are guided towards target dendrites by attractive and repulsive cues. Stable contacts between axons and dendrites result in the formation of functional synapses, which are highly elaborate asymmetric sites of neuron–neuron contact. The presynaptic side of the junction includes: (i) the active zone where neurotransmitter release occurs; (ii) a network of scaffolding proteins known as the cytomatrix of active zones; and (iii) a cluster of neurotransmitter-containing synaptic vesicles. Postsynaptic components include: (i) an accumulation of neurotransmitter receptors directly opposed to the active zone; and (ii) scaffolding proteins. At excitatory synapses these scaffolding proteins are known as the postsynaptic density (PSD); a distinct set of scaffolding proteins are present at inhibitory synapses. For synapses to function, all these components must be recruited and precisely aligned across the synaptic cleft, a 20-nm-wide extracellular space that separates two neurons at synaptic junctions. In view of this architecture, an appealing model of synapse assembly and maintenance invokes heterophilic presynaptic and postsynaptic transmembrane proteins that bind each other in the extracellular space and recruit additional proteins via their intracellular domains. Recently, several molecules, including synaptic cell-adhesion molecule (SynCAM), N-cadherin, neural cell-adhesion molecule (NCAM), Eph receptor tyrosine kinases, and neuroligins and neurexins, have been implicated in synapse formation and maintenance (Craig et al., in this issue). Here, we focus on the roles of two families of heterophilic adhesion molecules, neuroligins and neurexins, in trans-synaptic signaling. In particular, we address three emerging trends: (i) the potential of these two proteins to induce synapse assembly in cultured neurons; (ii) the modes of action of these proteins; and (iii) the implications of the effects of these proteins in the pathogenesis of cognitive disorders.

Section snippets

Neurexins and neuroligins

Neurexins were discovered as a result of their ability to bind α-latrotoxin, a component of black widow spider venom, which triggers massive neurotransmitter release [1]. Neurexins were hypothesized to act as cell-recognition molecules based on their structure: a single transmembrane region and an extracellular domain that is similar to laminin A, slit and agrin, proteins implicated in axon guidance and synaptogenesis 1, 2. There are three genes that encode α-neurexins and three genes that

Cell-adhesion and synapse-formation assays

Neuroligin-1 and β-neurexin, when expressed separately in heterologous cells, promote Ca2+-dependent adhesion between these cells [14]. Oligomerization of neuroligin molecules is necessary for this adhesion [13]. Remarkably, expression of neuroligins in fibroblast cells induces the formation of presynaptic terminals in axons that contact these cells 15, 16 and adhesion is required for this synaptogenic activity [13]. Such artificial hemi-synapses, composed of a fibroblast cell and neuronal

Function in neurons

Neuroligin-expressing fibroblasts can induce the formation of presynaptic terminals in contacting axons, and β-neurexin-expressing fibroblasts can induce the formation of postsynaptic sites in contacting dendrites, but can the two molecules form new synaptic sites at neuron–neuron contacts? Neuroligin overexpression in neurons has indeed been found, in several studies, to enhance the number of synapses (identified by immunostaining for presynaptic and postsynaptic proteins) (Table 1).

Presynaptic terminal assembly

The presynaptic signaling events induced by neurexins are currently unknown. Within minutes of contact between axons and dendrites, packets of active zone proteins arrive at a nascent synapse [23]. This is followed by arrival of synaptic vesicles, after which activity-dependent vesicle cycling occurs [24]. How might neurexins promote these events? One hint comes from the observation that actin can be polymerized on the cytoplasmic tail of β-neurexins via interactions with Ca2+

Neuroligins and autism

A change in the E/I-ratio has been suggested to correlate with autism and several other neurological disorders [55]. Mutations in the genes encoding neuroligin-3 and -4 on the X chromosome and the gene encoding neuroligin-4Y on the Y chromosome 8, 9 have been linked to cases of autism in several studies (Table 2), although multiple genes, in addition to neuroligins, are linked to autism. In addition, PSD95 has been implicated in a variety of disorders including autism [52]. These observations

Molecular mechanisms: future questions

The remarkable recent progress in the study of the neuroligin–neurexin interaction raises several interesting questions. For example, do different isoforms of neuroligins and neurexins confer specificity through different binding affinities or localizations? What is the sequence of events in the assembly of presynaptic and postsynaptic proteins downstream of neuroligin–neurexin and how does signaling mediate these events? How dynamic are proteins at synapses? Is there constant turnover,

Neuroligins and neurexins in the brain: what can we expect?

Perhaps the most interesting question is how neuroligins and neurexins function in the intact brain. Are neuroligins and neurexins active only during initial synapse formation or are they engaged during the modification of existing synapses in adulthood? Neuroligin-2 levels are subject to estrogen control in the brain, suggesting that regulation of expression levels has a role in neuroligin function in vivo [67]. Autistic individuals are predominantly impaired in language and social skills and

Acknowledgements

We are grateful to Meyer Jackson, Peter Scheiffele, Max Ulbrich and Xue Han for comments on the manuscript, and to J. Kirsch for support.

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