Neuroligins provide molecular links between syndromic and nonsyndromic autism - PubMed (original) (raw)
Review
Neuroligins provide molecular links between syndromic and nonsyndromic autism
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.
Figures
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. 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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References
- Miles JH. Autism spectrum disorders--a genetics review. Genet Med. 2011;13:278–294. published online EpubApr (10.1097/GIM.0b013e3181ff67ba). - PubMed
- Schaaf CP, Zoghbi HY. Solving the autism puzzle a few pieces at a time. Neuron. 2011;70:806–808. published online EpubJun 9 (S0896-6273(11)00443-0 [pii]10.1016/j.neuron.2011.05.025). - PubMed
- Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Gunel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Jr, Geschwind D, Roeder K, Devlin B, State MW. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70:863–885. published online EpubJun 9 (S0896-6273(11)00374-6 [pii] 10.1016/j.neuron.2011.05.002). - PMC - PubMed
- Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–241. published online EpubMay 10 (nature10945 [pii] 10.1038/nature10945). - PMC - PubMed
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