HAJRI M., HALAYEM S., LAKHAL M.H., MANSOURI A., ABBES Z., OTHMAN S., BOUDEN A.

Advancements in human genetics are revealing a large number of genetic variants involved in Autism spectrum disorder (ASD). This genetic variability affects mostly proteins involved in synaptic function.

The Medline database was searched using the following keywords: ‘synapses’; ‘autism’. Animal as well as human models of ASD were included.

Nowadays, ASD are considered genetically influenced neurodevelopmental disorders, with abundant evidence pointing to dysfunction at the level of the synapse in the early stages of cerebral development. Potential mechanisms underlying ASD are neuroanatomical abnormalities, extracellular factors, excitatory and inhibitory imbalance and synaptic signaling.

Mutations of Tsc1 (tuberous sclerosis 1) and nlgn3 (neuroligin3) lead to alterations of synapses in the cerebellum and could explain signs of autism in mice.

Growth factors and neurotrophic factors are associated with ASD such as: HGF, BDNF and WNT2.

Defects in synaptic proteins would lead to defective transmissions at excitatory and inhibitory synapses, a key mechanism implicated in ASD. Synaptic molecules involved: neuroligin, neurexin, shank, but also Glutamatergic system, GABAergic system and Serotonergic system.

NF1 (Neurofibromin 1), TSC1/TSC2 (tuberous sclerosis complex 1 and 2), and PTEN(phosphatase end tensin homolog) are tumor suppressors genes associated with ASD.

An alternative but not mutually exclusive hypothesis is that environmental factors interact with genetic susceptibilities to influence ASD risk, clinical phenotype and/or treatment outcome.