NLGs interact with Nrxs trans-synaptically. NLG-dependent control of synaptic activity increases the abundance of AMPA-type ionotropic glutamate receptors on the postsynaptic membrane by reducing the abundance of mGluRs (19). Postsynaptic mGluRs, which are activated by presynaptic release of glutamate, mediate long-term depression (LTD), which involves the endocytosis of AMPA receptors. FMRP1 binds to polysome-associated mRNAs and inhibits synthesis of certain proteins that enhance endocytosis of AMPA receptors. FMRP1-driven blockage of translation is removed by mGluR activation, which triggers induction of LTD. In FMRP1-knockout mice, mGluR-mediated LTD is enhanced similarly to that in NLG3-knockout mice (24). TSC1 and 2 (TSC1/2), which are encoded by the genes mutated in Tuberous Sclerosis, inhibit mTOR-dependent synthesis of proteins at the synapse that induce AMPA receptor endocytosis (21).