Genetic evidence for a protein-kinase-A-mediated presynaptic component in NMDA-receptor-dependent forms of long-term synaptic potentiation

The synaptic vesicle protein Rab3A is a small GTP-binding protein that interacts with rabphilin and RIM1 alpha, two presynaptic substrates of protein kinase A (PKA). Mice lacking RIM1 alpha and Rab3A have a defect in PKA-dependent and NMIDA receptor (NMDAR)independent presynaptic long-term potentiation (LTP) at hippocampal mossy-fiber and cerebellar parallel-fiber synapses. In contrast, the NMDAR-dependent and PKA-independent early phase of LTP at hippocampal CA3-CA1 synapses does not require these presynaptic proteins. Here, we ask whether Rab3A and RIM1 alpha participate in forms of LTP that require both PKA and NMIDAR activation. We find that Rab3A is necessary for corticoamygdala LTP and late-phase LTP at CA3-CA1 synapses, two forms of LTP that require NMIDAR and PKA activation. The latter form of LTP also requires RIM1 alpha. These results provide genetic evidence that presynaptic proteins are required in LTP induced through the postsynaptic activation of NMDARs. Thus Rab3A and its effectors are general modules for four distinct types of PKA-dependent LTP in the brain.