Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.

The C-terminal domain of NLG1 is sufficient to enhance spine and synapse number and to modulate synaptic plasticity, and it exerts these effects via its interaction with SPAR and the subsequent activation of LIMK1/cofilin-mediated actin reorganization.

Highlights d Splicing of the GluN1 exon 5-encoded N1 cassette alters allosteric modulation in vivo d Synapses of N1-containing NMDARs show reduced longterm potentiation d Mice lacking the N1 cassette have improved spatial memory acquisition and recall d iPSC-derived neurons in autism spectrum disorder show traits of N1-lacking GluN1