mTOR signaling is a major molecular pathway that controls activity-dependent protein synthesis in dendrites of hippocampal neurons.Previous studies revealed that TSC2, a GTPase-activating protein, inhibits mTOR.Here, we show that glutamate stimulation down-regulates TSC2 protein in cortical cultures by activating NMDA receptors.Interestingly, mTOR inhibitor rapamycin blocks the glutamate-induced TSC2 down-regulation; this finding suggests the existence of an mTOR signaling-mediated negative-feedback regulation of TSC2.