Protein synthesis as a modifiable target for autism-related dendritic spine pathophysiologies.

Autism spectrum disorder (ASD) is increasingly recognized as a condition of altered brain connectivity. As synapses are fundamental subcellular structures for neuronal connectivity, synaptic pathophysiology has become one of central themes in autism research. Reports disagree upon whether the density of dendritic spines, namely excitatory synapses, is increased or decreased in ASD and whether the protein synthesis that is critical for dendritic spine formation and function is upregulated or downregulated. Here, we review recent evidence supporting a subgroup of ASD models with decreased dendritic spine density (hereafter ASD-DSD), including Nf1 and Vcp mutant mice. We discuss the relevance of branched-chain amino acid (BCAA) insufficiency in relation to unmet protein synthesis demand in ASD-DSD. In contrast to ASD-DSD, ASD models with hyperactive mammalian target of rapamycin (mTOR) may represent the opposite end of the disease spectrum, often characterized by increases in protein synthesis and dendritic spine density (denoted ASD-ISD). Finally, we propose personalized dietary leucine as a strategy tailored to balancing protein synthesis demand, thereby ameliorating dendritic spine pathophysiologies and autism-related phenotypes in susceptible patients, especially those with ASD-DSD.