The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders - PubMed (original) (raw)

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The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders

Catalina Betancur et al. Trends Neurosci. 2009 Jul.

Abstract

Recent advances in genetics and genomics have unveiled numerous cases of autism spectrum disorders (ASDs) associated with rare, causal genetic variations. These findings support a novel view of ASDs in which many independent, individually rare genetic variants, each associated with a very high relative risk, together explain a large proportion of ASDs. Although these rare variants impact diverse pathways, there is accumulating evidence that synaptic pathways, including those involving synaptic cell adhesion, are disrupted in some subjects with ASD. These findings provide insights into the pathogenesis of ASDs and enable the development of model systems with construct validity for specific causes of ASDs. In several neurodevelopmental disorders frequently associated with ASD, including fragile X syndrome, Rett syndrome and tuberous sclerosis, animal models have led to the development of new therapeutic approaches, giving rise to optimism with other causes of ASDs.

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Figures

Figure 1.

Figure 1.

At the synapses, cell adhesion molecules connect presynaptic and postsynaptic sites through homophilic (e.g., caherins, protocadherins and L1CAM) and heterophilic (e.g., neuroligin-neurexin, CNTNAP2 and contactins) interactions, and play roles in synapse development, function and plasticity. These cell adhesion molecules also interact with several cytoplasmic proteins, namely synaptic scaffolding proteins (e.g., postsynaptic density protein 95 [PSD95] and SHANK, which in turn serve as platforms for signaling molecules), cytoskeletal proteins (e.g., ankryin, ezrin, catenin, actin and spectrin) and signaling molecules (e.g., calmodulin-dependent serine kinase [CASK], src family kinases, and mitogen-activated protein kinase [MAPK] cascade proteins including TAO kinase 2 [TAOK2] and MAPK3), all of which are involved in synapse assembly and shape, function, and plasticity. Expression of cell adhesion molecules can determine the chemical nature of synapses and the downstream signaling. The expression and localization of cell adhesion molecules are modulated by neuronal activity, leading to regulation of synaptic strength and sculpting of the molecular components of the synapse. The proteins whose genes have been shown to be involved in ASD and/or ID are indicated in red. The question marks shown after spectrin highlight the fact that the functional meaning of the interaction between this protein and protocadherins is unclear.

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