Targeting Rac1 and other Actin Cytoskeleton Regulators as a possible Therapeutic Strategy to Rescue Autism-like Symptoms

Synaptic transmission and dendritic spine (DS) formation in excitatory synapses are finely regulated by many membrane receptors and intracellular proteins, most of them participating in the formation of the post-synaptic density (PSD), a membrane-free organelle adjacent to the neuronal post-synaptic plasmatic membrane. Rac1 belongs to the small Rho GTPases family, and is proven to play a crucial role in the regulation of actin cytoskeleton in DSs, eventually affecting their architecture. At synapses, it is finely regulated by the presence of Rac1-Guanosine Exchange Factor (GEF) proteins, as Tiam1 or Dock4, and Rac1-GTPase Activating Proteins (GAP), as Bcr/Abr, inhibiting and activating it, respectively. Defects in the expression of Rac1 itself or of its regulatory proteins are associated with neurodevelopmental disorders, including autism spectrum disorders (ASD). Intriguingly, mice lacking the Rac1-GEF Dock4 in pyramidal hippocampal CA1 neurons recapitulated Autism-like symptoms, including social preference impairments, augmented anxiety levels, and repetitive stereotyped behaviors, all accompanied by a dramatic reduced excitatory synapses transmission, number of glutamatergic receptors’ subunits and Rac1 activity. Moreover, comparable results were obtained following analogous behavioral tests in the absence of Shank3, being a well-known ASD-causative gene. The absence of Shank3 and Dock4 negatively affects Rac1 functioning within the PSD, causing ASD-associated behaviors. The overexpression of Rac1 or of its constitutively-active form in hippocampal neurons increased social preference and restored excitatory synaptic transmission. These data confirmed Rac1 fundamental contribution to synaptogenesis and synaptic plasticity mechanisms, and opened a new therapeutic window for the treatment of autism.