Neuroligins provide molecular links between syndromic and nonsyndromic autism - PubMed (original) (raw)

Review

Sandeep K Singh et al. Sci Signal. 2013.

Abstract

Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and nonsyndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and nonsyndromic autism genes were lacking until studies aimed at understanding the role of trans-synaptic adhesion molecule neuroligin, which is associated with nonsyndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism.

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Figures

Fig. 1

Fig. 1. Neuroligin function at the synapse links syndromic and non-syndromic autism

NLGs interact with Nrxs trans-synaptically. NLG-dependent control of synaptic activity increases the abundance of AMPA-type ionotropic glutamate receptors on the postsynaptic membrane by reducing the abundance of mGluRs (19). Postsynaptic mGluRs, which are activated by presynaptic release of glutamate, mediate long-term depression (LTD), which involves the endocytosis of AMPA receptors. FMRP1 binds to polysome-associated mRNAs and inhibits synthesis of certain proteins that enhance endocytosis of AMPA receptors. FMRP1-driven blockage of translation is removed by mGluR activation, which triggers induction of LTD. In FMRP1-knockout mice, mGluR-mediated LTD is enhanced similarly to that in NLG3-knockout mice (24). TSC1 and 2 (TSC1/2), which are encoded by the genes mutated in Tuberous Sclerosis, inhibit mTOR-dependent synthesis of proteins at the synapse that induce AMPA receptor endocytosis (21).

Fig. 2

Fig. 2. Presynaptic NLGs control synaptic vesicle release kinetics in C. elegans neuromuscular junction

In the C. elegans neuromuscular junction, MEF-2 activity in the muscle inhibits presynaptic release of neurotransmitter in a retrograde manner that involves an interaction between postsynaptic NRX and presynaptic NLG.

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