One form of synaptic plasticity that is sensitive to alterations in protein synthesis is mGluR-LTD.44 Increases in bulk protein synthesis, observed in mouse models of FXS and Syngap1 haploinsufficiency, coincide with an elevation in mGluR-LTD that is no longer gated by new protein synthesis.27,45,46 In contrast, decreases in bulk protein synthesis, as observed in Tsc2 heterozygous mice, lead to an impairment in mGluR-LTD.42 Together they define an axis of synaptic pathophysiology, where deviations in protein synthesis can be used to predict disease related cellular abnormalities. The gene discussed is TSC2; the disease is fragile X syndrome.