A synaptic trek to autism

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Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN–NLGN–SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.

Introduction

Autism affects about 0.7% of children and is characterized by deficits in social communication, absence or delay in language, and stereotyped and repetitive behaviors. Beyond this unifying definition, lies a spectrum of disorders/conditions, ranging from severe impairments to mild personality traits. Autism spectrum disorders (ASD) are diagnosed before three years of age, a period characterized by intense synaptogenesis in the human brain [1]. This review reports recent genetic and neurobiological findings that highlight two routes leading to ASD: abnormal cellular/synaptic growth and imbalance between inhibitory and excitatory synaptic currents.

Section snippets

Abnormal cellular/synaptic growth in ASD

The hypothesis that abnormal cellular/synaptic growth may increase the risk of having ASD, was first suggested by the recurrent observation of macrocephaly in 10–30% of the patients with ASD [2, 3, 4]. The head circumference may be normal at birth, but during the first four years of life, an overgrowth of the brain is observed [5, 6]. The nature of the macrocephaly  too many neurons, glial cells, synapses, or larger cells  remains difficult to establish. However, studies on neurofibromatosis,

Abnormal balance between inhibitory and excitatory currents in ASD

The possibility that alteration of synaptic functions could lead to ASD was first indicated by the phenotypic overlap between autism, fragile X syndrome, and Rett syndrome [12, 13]. In addition, the key role of the excitatory/inhibitory currents in ASD was further supported by the observation that 10–30% of patients with ASD have epilepsy [14]. The synaptic hypothesis was confirmed by the identification of mutations affecting the postsynaptic cell adhesion molecules Neuroligins (NLGN) in

Atypical neuronal networks in ASD

In the human cerebral cortex, the first synapses are evident at the 40th day after conception. Thereafter, the rate of synapse formation and pruning exhibit distinct phases, the most dramatic change takes place during the perinatal period (Figure 1). During the first three years of life, synaptic contacts are formed, but only some will be stabilized. This selection process represents a key step in the cognitive development of the child. The NLGN–NRXN–SHANK pathway is probably required during

New routes to ASD?

Two main pathways were identified in the susceptibility to ASD, but most probably many other tracks can lead to this complex syndrome. Furthermore, even when a pathway is identified, the diversity of genotype–phenotype relationships observed in patients with ASD indicates that other modulators such as serotonin and/or melatonin may play crucial roles in the onset and severity of ASD [48, 49•]. The recent results have shed light on the origin of ASD and we are confident that new pathways will be

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by the Pasteur Institute, University Denis Diderot Paris 7, INSERM, CNRS, Assistance Publique-Hôpitaux de Paris, FP6 ENI-NET, FP6 EUSynapse, Fondation Orange, Fondation de France, and Fondation pour la Recherche Médicale, Fondation FondaMentale.

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