Major progress has been carried out in the last two decades in the identification of genetic alterations associated with mental retardation and autism spectrum disorders. In many instances these defects concern genes coding for synaptic proteins or proteins involved in regulation of synaptic properties. Analyses of the underlying mechanisms using gain and loss of function approaches have revealed alterations of spine morphology, density or plasticity, raising the possibility that these disorders result from synaptopathies. Also the multiplicity of genes and proteins involved points to the implication of specific signaling pathways among which small GTPases appear to play a central role. We review here this evidence and discuss the mechanisms through which they might lead to synaptic network dysfunction.