Control of neural circuit formation by leucine-rich repeat proteins

doi:10.1016/j.tins.2014.07.004

Trends in Neurosciences

Volume 37, Issue 10, October 2014, Pages 539-550

https://doi.org/10.1016/j.tins.2014.07.004 Get rights and content

Highlights

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Leucine-rich repeat (LRR) proteins regulate the development, function, and plasticity of excitatory and inhibitory synapses.
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Postsynaptic LRR proteins interact with key presynaptic receptors to promote pre- and postsynaptic differentiation.
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Distinct LRR proteins are expressed in different cell types in the central nervous system (CNS).
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LRR protein dysfunction may disrupt the excitation/inhibition balance and contribute to neuropsychiatric disorders.

The function of neural circuits depends on the precise connectivity between populations of neurons. Increasing evidence indicates that disruptions in excitatory or inhibitory synapse formation or function lead to excitation/inhibition (E/I) imbalances and contribute to neurodevelopmental and psychiatric disorders. Leucine-rich repeat (LRR)-containing surface proteins have emerged as key organizers of excitatory and inhibitory synapses. Distinct LRR proteins are expressed in different cell types and interact with key pre- and postsynaptic proteins. These protein interaction networks allow LRR proteins to coordinate pre- and postsynaptic elements during synapse formation and differentiation, pathway-specific synapse development, and synaptic plasticity. LRR proteins, therefore, play a critical role in organizing synaptic connections into functional neural circuits, and their dysfunction may contribute to neuropsychiatric disorders.

Section snippets

LRR proteins and the organization of functional neural circuits

The function of neural circuits depends on the precise connectivity between populations of neurons. In the central nervous system (CNS) this is mediated by glutamatergic and GABAergic synapses, and there is emerging evidence that disruptions in the formation or function of excitatory or inhibitory synapses lead to excitation/inhibition (E/I) imbalances, which characterize several psychiatric and neurodevelopmental disorders 1, 2, 3, 4, 5, 6, 7, 8. These considerations underscore the importance

LRR proteins as regulators of synapse development

Recent studies have identified several closely related LRR protein families as regulators of synapse development. A simple in vitro assay, which tests the ability of neurons to form synapses onto co-cultured heterologous cells expressing candidate genes 10, 11, has been instrumental in identifying synapse-organizing or synaptogenic LRR proteins. The elucidation of their trans-synaptic interactions has highlighted a common theme of diverse postsynaptic ligands coupling to a limited repertoire of

LRR transmembrane neuronal proteins control excitatory synapse development via distinct presynaptic partners

Since their original identification as synaptogenic proteins in a co-culture assay-based expression screen [12], LRR transmembrane neuronal proteins (LRRTMs) 1–4 have rapidly become the most intensively studied family of LRR-containing synaptic organizers. LRRTMs are type I transmembrane proteins with an extracellular LRR domain and a C-terminal postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (zo-1) (PDZ) interaction site (

Slit- and Trk-like proteins regulate excitatory and inhibitory synapse development via receptor protein tyrosine phophatases

Based on their structural similarity to LRRTMs (Figure 1B), Slit- and Trk-like proteins (Slitrks) 1–6 were predicted to have synaptogenic properties in a bioinformatics search [12]. When tested in the co-culture assay, Slitrk2 expressed on the surface of fibroblasts indeed induced presynaptic differentiation in contacting axons [12]. Subsequent studies showed that all Slitrk family members have similar activity [28]. Slitrks are broadly expressed in the hippocampus (Figure 4), and are

Netrin-G ligands regulate input-specific synapse development

Netrin-G ligands (NGL)1–3 are structurally related to LRRTMs and Slitrks, but contain an additional Ig domain in their extracellular region (Figure 1C). Their identification as PSD-95 interactors in yeast two hybrid screens suggested a role at synapses, and biochemical fractionation and immuno-EM confirmed that NGL-2 and -3 localize to the postsynaptic density 33, 39. All NGLs induce presynaptic differentiation in co-culture assays, with NGL-3 having markedly stronger effects than NGL-1 or -2 33

Fibronectin leucine-rich repeat transmembrane proteins interact with latrophilin, a presynaptic adhesion GPCR

Similar to LRRTMs, Slitrks, and NGLs, fibronectin leucine-rich repeat transmembrane proteins (FLRT)1–3 bind to a presynaptic receptor that interacts with multiple postsynaptic ligands. In the hippocampus, FLRT2 and FLRT3 show complementary expression patterns (Figure 4), whereas FLRT1 is only weakly expressed. The role of FLRTs in synaptic development is best characterized for FLRT3, an adhesion molecule present at excitatory synapses and in postsynaptic density fractions [52]. Affinity

Other LRR proteins regulating excitatory and inhibitory synapse development

A surprising discovery from a co-culture-based expression screen is TrkC [32], the tyrosine kinase receptor for the neurotrophin NT-3, which broadly regulates neural development [75]. TrkC is the only Trk receptor that induces presynaptic differentiation in co-cultures, and this requires the LRR and first Ig domain, which are not involved in NT-3 binding. TrkC trans-synaptically interacts with RPTPσ, but not with RPTPδ or LAR, and this interaction is required for excitatory synapse development,

LRR proteins as regulators of synaptic function and plasticity

The LRR proteins discussed thus far all have synaptogenic effects in cultured neurons. An exception is Elfn1, an LRR protein with a domain organization similar to FLRTs, but containing a longer cytoplasmic tail. Elfn1 does not induce presynaptic differentiation in co-culture assays or affect synapse number when overexpressed in cultured neurons [81]. Rather, Elfn1 trans-synaptically instructs presynaptic neurotransmitter release properties. Elfn1 is expressed in somatostatin-positive

Concluding remarks

There has been tremendous progress in the past few years in the identification of novel LRR-containing synaptic adhesion molecules, the elucidation of their trans-synaptic interactions, and the understanding of their role in the development and plasticity of synapses. Several families of postsynaptic LRR proteins, with similar domain organization, but with distinct cell type-specific expression, have now been identified. The significance of such diversity of LRR proteins, especially at

Acknowledgments

Work in the authors’ labs on LRR proteins is supported by an ERC Starting Grant (#311083) and FWO Odysseus Grant (J.d.W.), and NIH grant R01NS067216 (A.G.).

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Given an important role of AMPAR in chronic pain-related syndromes [4,16–18], we investigated whether and how spinal caspase-3 mediates fracture-associated postoperative pain. Leucine-rich repeat transmembrane proteins (LRRTMs) are synaptic cell adhesion molecules that drive excitatory synapse formation as well as affect synaptic function [19,20]. LRRTM1 has been recognized for its prominent role in the maintenance of AMPAR density at synapses and long-term potentiation (LTP) [21,22].
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A model of tibial fracture with intramedullary pinning in mice was established for the induction of postoperative pain, verified by measurement of mechanical paw withdrawal threshold and cold scores response to acetone. The caspase-3 specific inhibitor, recombinant caspase-3 and LRRTM1 knockdown by shRNA were utilized for the investigation of pathogenesis as well as the prevention of allodynia. Also, the activity of caspase-3 and the expression of LRRTM1 in the spinal dorsal horn were examined by Western blot and RT-qPCR.
This study reported that tibial fracture and orthopedic surgery produced long-lasting mechanical allodynia and cold allodynia, along with the up-modulation of spinal caspase-3 activity (but not caspase-3 expression) and LRRTM1 expression. Spinal caspase-3 inhibition prevented fracture-associated behavioral allodynia in a dose-dependent manner. Caspase-3 inhibitor also reduced the spinal increased LRRTM1 level after tibial fracture with pinning. Spinal LRRTM1 deficiency impaired fracture-caused postoperative pain. Intrathecal recombinant caspase-3 facilitated acute pain hypersensitivity and spinal LRRTM1 expression in naïve mice, reversing by LRRTM1 knockdown.
Our current results demonstrate the spinal up-regulation of LRRTM1 by caspase-3 activation in the development of tibial fracture-associated postoperative pain in mice.
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Social affiliative behaviors—engagement in positive (i.e., nonaggressive) social approach and reciprocal social interactions with a conspecific—comprise a construct within the National Institute of Mental Health Research Domain Criteria Social Processes Domain. These behaviors are disrupted in multiple human neurodevelopmental and neuropsychiatric disorders, such as autism, schizophrenia, social phobia, and others. Human genetic studies have strongly implicated synaptic cell adhesion molecules (sCAMs) in several such disorders that involve marked reductions, or other dysregulations, of social affiliative behaviors. Here, we review the literature on the role of sCAMs in social affiliative behaviors. We integrate findings pertaining to synapse structure and morphology, neurotransmission, postsynaptic signaling pathways, and neural circuitry to propose a multilevel model that addresses the impact of a diverse group of sCAMs, including neurexins, neuroligins, protocadherins, immunoglobulin superfamily proteins, and leucine-rich repeat proteins, as well as their associated scaffolding proteins, including SHANKs and others, on social affiliative behaviors. This review finds that the disruption of sCAMs often manifests in changes in social affiliative behaviors, likely through alterations in synaptic maturity, pruning, and specificity, leading to excitation/inhibition imbalance in several key regions, namely the medial prefrontal cortex, basolateral amygdala, hippocampus, anterior cingulate cortex, and ventral tegmental area. Unraveling the complex network of interacting sCAMs in glutamatergic synapses will be an important strategy for elucidating the mechanisms of social affiliative behaviors and the alteration of these behaviors in many neuropsychiatric and neurodevelopmental disorders.
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Synaptic adhesion proteins play a critical role in the formation and maintenance of synapses in the developing nervous system. Errors in synaptic adhesion constitute the molecular basis of many neuropsychiatric disorders, including schizophrenia, bipolar disorder, Tourette syndrome, and autism. Slit- and Trk-like proteins (Slitrks) are a family of leucine-rich repeat containing transmembrane proteins that promote synaptogenesis. These proteins localize to the postsynaptic density, where they induce synapse formation via trans-synaptic interactions with receptor protein tyrosine phosphatases. While trans-synaptic binding partners of Slitrks have been reported, little is known about the intracellular proteins that associate with Slitrks. Here we report an interaction between Slitrk2 and members of the PSD-95 subfamily of membrane associated guanylate kinases (MAGUKs). Coimmunoprecipitation from postnatal mouse brain indicates that PSD-93 and PSD-95 associate with Slitrk2 in vivo. Mapping analysis in yeast demonstrates that Slitrk2 interacts directly with PSD-95 via a non-canonical Src homology 3 (SH3) domain binding motif that associates with the SH3 domain of PSD-95. We also show that PSD-95 induces robust clustering of Slitrk2 in 293T cells, and deletion of the SH3 domain in PSD-95 or the SH3 domain binding motif in Slitrk2 reduces this clustering. These data confirm PSD-95 as the first known intracellular binding partner of Slitrk2. Future studies will examine if Slitrk-MAGUK interactions mediate localization of Slitrks to synaptic sites and facilitate recruitment of additional intracellular signaling molecules involved in postsynaptic differentiation.
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Furthermore, disrupting SALM5 dimerization impaired its function in inducing presynaptic differentiation [30••,31••]. Besides SALMs, a large number of LRR-containing synaptic adhesion molecules such as the LRRTMs [40], netrin-G ligands (NGLs) [41] and Slitrks [42] have been identified to be involved in synapse formation and maintenance. Recent crystal structure of LRRTM2 in complex with neurexin revealed that the functional unit of LRRTM2 for synaptogenesis is a monomer [43], although SEC-MALLS analysis for LRRTM2 indicated species with a higher than monomer molecular weight [44].
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Trends in Neurosciences

Feature ReviewSpecial Issue: Circuit Development and RemodelingControl of neural circuit formation by leucine-rich repeat proteins

Highlights

Section snippets

LRR proteins and the organization of functional neural circuits

LRR proteins as regulators of synapse development

LRR transmembrane neuronal proteins control excitatory synapse development via distinct presynaptic partners

Slit- and Trk-like proteins regulate excitatory and inhibitory synapse development via receptor protein tyrosine phophatases

Netrin-G ligands regulate input-specific synapse development

Fibronectin leucine-rich repeat transmembrane proteins interact with latrophilin, a presynaptic adhesion GPCR

Other LRR proteins regulating excitatory and inhibitory synapse development

LRR proteins as regulators of synaptic function and plasticity

Concluding remarks

Acknowledgments

Cell

Cell

Neuron

Genomics

Neuron

Neuron

Cell

Cell

Cell

Curr. Opin. Neurobiol.

Neuron

Neuron

Neuron

Neuron

Trends Neurosci.

Biol. Psychiatry

J. Biol. Chem.

Mol. Cell. Neurosci.

Genomics

J. Mol. Biol.

Mech. Dev.

Neuron

Neuron

Neuron

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell Rep.

J. Biol. Chem.

Dev. Biol.

Curr. Biol.

Neuron

Gene

J. Biol. Chem.

Neuron

Neuron

Neuroscience

Biol. Psychiatry

Neuron

A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice

Science

Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function

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

Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism

Science

Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

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

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Nature

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Nature

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

Nat. Genet.

The extracellular leucine-rich repeat superfamily; a comparative survey and analysis of evolutionary relationships and expression patterns

BMC Genomics

Mixed-culture assays for analyzing neuronal synapse formation

Nat. Protoc.

LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development

J. Neurosci.

Feature Review
Special Issue: Circuit Development and Remodeling
Control of neural circuit formation by leucine-rich repeat proteins