Synapse development in health and disease

doi:10.1016/j.gde.2011.01.002

Current Opinion in Genetics & Development

Volume 21, Issue 3, June 2011, Pages 256-261

https://doi.org/10.1016/j.gde.2011.01.002 Get rights and content

Recent insights into the genetic basis of neurological disease have led to the hypothesis that molecular pathways involved in synaptic growth, development, and stability are perturbed in a variety of mental disorders. Formation of a functional synapse is a complex process requiring stabilization of initial synaptic contacts by adhesive protein interactions, organization of presynaptic and postsynaptic specializations by scaffolding proteins, regulation of growth by intercellular signaling pathways, reorganization of the actin cytoskeleton, and proper endosomal trafficking of synaptic growth signaling complexes. Many neuropsychiatric disorders, including autism, schizophrenia, and intellectual disability, have been linked to inherited mutations which perturb these processes. Our understanding of the basic biology of synaptogenesis is therefore critical to unraveling the pathogenesis of neuropsychiatric disorders.

Introduction

The formation of a functional, mature neuronal synapse requires a host of molecular players to mediate coordinated presynaptic and postsynaptic growth. In recent years, clinically diverse disorders such as autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID) have been linked to dysfunction of a number of proteins implicated in synaptic development [1, 2]. For example, deletions of neurexin-1α, a synaptic cell adhesion protein, were initially identified by large-scale genetic screens in patients with autism and schizophrenia, and subsequently found in patients with severe ID and epilepsy [3]. Mutations in genes encoding the SHANK postsynaptic scaffolding protein family were first identified in a patient with ID, and later associated with autism and schizophrenia [4, 5]. As the number of genes contributing to neuropsychiatric disorders has grown, it has become increasingly clear that pathways contributing to synaptic development and activity-dependent growth are important in their etiology.

Here, we examine the genes implicated in synaptogenesis which have been associated with neurological disease. In particular, we highlight the role of these genes in synaptic cell adhesion, organization of presynaptic and postsynaptic specializations, growth signaling pathways, and endosomal function. Insights into the function of these genes at the Drosophila neuromuscular junction (NMJ) are emphasized, as this model glutamatergic synapse is well studied within the context of activity-dependent synaptic development.

Section snippets

Specification and stabilization of the synapse is mediated by cell adhesion proteins

One of the earliest steps in synaptogenesis is the induction and adhesion of precisely opposed presynaptic and postsynaptic domains. Multiple transsynaptic cell adhesion complexes operate in parallel to ensure proper synaptic alignment (Figure 1). Mutation of synaptic adhesion proteins has been linked to various neuropsychiatric disorders, indicating that abnormal formation or maintenance of synaptic contacts may be impaired in several neurological diseases [6]. Members of the cadherin and

Organization of presynaptic and postsynaptic domains by scaffolding proteins

Formation of a functional synapse requires assembly of synaptic proteins into domains specialized for neurotransmitter release and reception. Scaffolding proteins are critical mediators of this process on both sides of the synapse. Scaffolds are composed of multiple protein–protein interaction domains, and form a physical link between adhesion proteins, ion channels, neurotransmitter receptors, intercellular signaling cascades, and the actin cytoskeleton.

One of the strongest links between

Activity-dependent synaptic development depends on intercellular signaling pathways

Once a synapse is formed, neuronal activity plays an essential role in shaping and maintaining synaptic connections [32]. Anterograde and retrograde secreted signaling molecules, including the Wnts and BMPs, regulate synaptic growth (Figure 1) and may also contribute to the development of neurological disease. The Wnt family of signaling molecules participates in a broad range of processes, from neurogenesis to synaptic plasticity. Several Wnt pathway components have been implicated in the

Synaptic growth signaling requires proper endosomal trafficking

Regulation of endosomal traffic is a critical component of synaptic growth and development. Growth signals released during activity, such as the Wnts and BMPs described above, bind to synaptic transmembrane receptors and are internalized as receptor–ligand signaling complexes. These signaling complexes are transported within the endosomal system, in which receptors signal from an early endosome population before signal inactivation in the recycling endosome or lysosome (Figure 2). Many of the

Conclusion

Abnormal synaptic development is thought to underlie multiple neurodevelopmental disorders which present with clinically distinct phenotypes. Altered synaptic structure or function may also lead to changes in neuronal connectivity which predispose an individual to neurodegenerative disease. We have highlighted several genes implicated in neuropsychiatric disease which have defined roles in synaptic development. Mutations in different genes or gene combinations may lead to a similar disease

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.
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How do synaptic structural and functional changes correlate with memory? Cell interactions are known to play a key role in neural developmental events and in particular in building and maintaining synaptic structure and function (Melom and Littleton, 2011). Although these events are mostly relevant for development, they also occur in adult nervous tissue (Kolodkin and Tessier-Lavigne, 2011), and in both cases they correlate with the expression of cell adhesion molecules (CAMs) (Gerrow and El-Husseini, 2006; Margeta and Shen, 2010; Stagi et al., 2010).
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Synapse development in health and disease

Introduction

Section snippets

Specification and stabilization of the synapse is mediated by cell adhesion proteins

Organization of presynaptic and postsynaptic domains by scaffolding proteins

Activity-dependent synaptic development depends on intercellular signaling pathways

Synaptic growth signaling requires proper endosomal trafficking

Conclusion

References and recommended reading

Am J Hum Genet

Biochem Biophys Res Commun

Neuron

Trends Neurosci

Nature

Neuron

Cell

Neuron

Mol Psychiatry

Mol Autism

Nat Neurosci

Cell

Ann Neurol

Oncogene

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Nat Neurosci

Neuron

J Neurosci

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J Am Acad Child Adolesc Psychiatry

The genetics of neurodevelopmental disease

Curr Opin Neurobiol

Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation

Arch Gen Psychiatry

De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia

Proc Natl Acad Sci U S A

Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

Nat Genet

Cell adhesion, the backbone of the synapse: ‘vertebrate’ and ‘invertebrate’ perspectives

Cold Spring Harb Perspect Biol