A synaptic trek to autism
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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