The Role of Synaptic Cell Adhesion Molecules and Associated Scaffolding Proteins in Social Affiliative Behaviors

doi:10.1016/j.biopsych.2020.02.012

Biological Psychiatry

Volume 88, Issue 6, 15 September 2020, Pages 442-451

https://doi.org/10.1016/j.biopsych.2020.02.012 Get rights and content

Abstract

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.

Section snippets

Neurexins

Proteins of the neurexin family are key organizers of the synapse, with thousands of isoforms and multiple binding partners. Neurexins are present at presynaptic membranes of excitatory and inhibitory synapses (11,12) (see Figures 1 and 2). They have been shown to be involved in recruitment of synaptic vesicles to the presynaptic membrane for release and in triggering postsynaptic differentiation (11,13). Neurexins bind GABA_A (gamma-aminobutyric acid A) receptors in addition to other sCAMs,

Cadherins

There are over 100 members of the cadherin superfamily, defined by the presence of one or more of approximately 110 amino acid-long cadherin domains in their extracellular portions. Subfamilies of cadherins include the classical cadherins (including type I and type II cadherins), desmosomal cadherins, protocadherins, calsyntenins, and atypical/7-transmembrane cadherins. Cadherins have been implicated in pre- and postsynaptic organization and are likely to play key roles in synapse formation and

Immunoglobulin Superfamily

Many sCAMs belong to the IgSF, whose members are defined by the presence of extracellular Ig domains similar to those in antibodies, each comprising a sandwich of two β-sheets. Multiple members of this family have been implicated in synapse formation, maintenance, and plasticity (75). Unfortunately, few IgSF members have been examined in the social affiliation literature as of yet.

Chl1 is involved in synapse maintenance, via influences on presynaptic organization (76,77). CHL1 is expressed on

sCAM-Associated Scaffolding Proteins

Owing to limitations in space, the sCAM-associated scaffolding proteins, including the SHANK family, are discussed in detail in the Supplement.

Proposed Mechanistic Model

We propose that sCAMs affect social affiliation behavior via one or more of the following mechanisms: altered specificity during synaptogenesis, disrupted synaptic maturation, and/or altered synaptic pruning. According to our model, the net effect of these mechanisms is alteration in excitatory/inhibitory balance in circuits relevant to social affiliative behaviors (circuits including the mPFC, BLA, VTA, ACC, and hippocampus) (see Figure 3).

With a single exception (noted below), the following

Discussion

The overall patterns that we observed in the literature suggest that mutation/dysfunction of sCAM genes alters synaptic maturation, specificity, and pruning and leads to excitatory/inhibitory imbalance in several relevant brain regions, including the mPFC, BLA, VTA, and hippocampus. Moving forward, there is a need for studies of sCAM gene knockouts on additional genetic backgrounds, as well as a need for more comprehensive studies of mutations in the various sCAMs. Many published studies have

Acknowledgments and Disclosures

This work was supported by the Autism Spectrum Program of Excellence (Research Gift to the University of Pennsylvania, Daniel J. Rader, MB, and ESB, principal investigators); Pennsylvania Department of Health Grant Nos. SAP #4100042728 (to Robert T. Schultz, principal investigator) and 1P50MH096891 (to Raquel Gur, principal investigator) subproject 6773 (to ESB and TA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National

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ReviewThe Role of Synaptic Cell Adhesion Molecules and Associated Scaffolding Proteins in Social Affiliative Behaviors

Abstract

Section snippets

Neurexins

Cadherins

Immunoglobulin Superfamily

sCAM-Associated Scaffolding Proteins

Proposed Mechanistic Model

Discussion

Acknowledgments and Disclosures

Mol Cytogenet

Brain Res

Biol Psychiatry

Cell

J Biol Chem

Neuron

Neuron

Neuron

Biochem Biophys Res Commun

Neuron

Genomics

Neuron

Cell

Mol Cell Neurosci

Neuropharmacology

Eur J Cell Biol

Behav Brain Res

Behav Brain Res

Neuron

Curr Opin Neurobiol

Mol Cell Neurosci

Behav Brain Res

Cell

Neuroscience

Biol Psychiatry

Biol Psychiatry

Trends Neurosci

Neuron

J Biol Chem

Mol Cell Neurosci

Neuron

Mol Cell Neurosci

Biochem Biophys Res Commun

Brain Res

J Biol Chem

Neuroscience

Trends Neurosci

FEBS Lett

Cell Rep

Neuron

Neuroligins and neurexins link synaptic function to cognitive disease

Nature

Neurexins and neuropsychiatric disorders

Neurosci Res

An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia

Mol Psychiatry

Microduplication of 3p263 in nonsyndromic intellectual disability indicates an important role of CHL1 for normal cognitive function

Neuropediatrics

Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk

PLoS One

The emerging role of SHANK genes in neuropsychiatric disorders

Dev Neurobiol

Sociability and preference for social novelty in five inbred strains: An approach to assess autistic-like behavior in mice

Genes Brain Behav

Neurexins: Synaptic cell surface proteins related to the cL-latrotoxin receptor and laminin

Science

Neurexin mediates the assembly of presynaptic terminals

Nat Neurosci

A stoichiometric complex of neurexins and dystroglycan in brain

J Cell Biol

Review
The Role of Synaptic Cell Adhesion Molecules and Associated Scaffolding Proteins in Social Affiliative Behaviors