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Published online on June 20, 2005, 10.1073/pnas.0503777102
PNAS | June 28, 2005 | vol. 102 | no. 26 | 9365-9370


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

Yan-You Huang *, Stanislav S. Zakharenko *, Susanne Schoch {dagger} {ddagger}, Pascal S. Kaeser {dagger}, Roger Janz {dagger}, §, Thomas C. Südhof {dagger}, Steven A. Siegelbaum *, ¶, and Eric R. Kandel *, ¶, ||

*Center for Neurobiology and Behavior, New York State Psychiatric Institute and Howard Hughes Medical Institute, Columbia University Medical Center, 722 West 168th Street, New York, NY 10032; {dagger}Center for Basic Neuroscience, Howard Hughes Medical Institute, and Department of Molecular Genetics, University of Texas Southwestern Medical School, Dallas, TX 75390; and §Department of Neurobiology and Anatomy, University of Texas Health Sciences Center, Houston, TX 77030

Contributed by Eric R. Kandel, May 10, 2005

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 NMDA 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 NMDAR activation. We find that Rab3A is necessary for corticoamygdala LTP and late-phase LTP at CA3–CA1 synapses, two forms of LTP that require NMDAR 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.

long-term potentiation | protein kinase A | RIM | Rab3A

Author contributions: Y.-Y.H., T.C.S., S.A.S., and E.R.K. designed research; Y.-Y.H., S.S.Z., S.S., P.S.K., and R.J. performed research; Y.-Y.H. and S.S.Z. analyzed data; and Y.-Y.H., S.S.Z., T.C.S., S.A.S., and E.R.K. wrote the paper.

Abbreviations: 6-APB, 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; D-APV, D-2-amino-5-phosphonovaleric acid; SP-cAMPS, SP-adenosine 3',5'-cyclic monophosphorothioate; EPSP, excitatory postsynaptic potential; fEPSP, field EPSP; LTP, long-term potentiation; E-LTP, early-phase LTP; L-LTP, late-phase LTP; NDMAR, NDMA receptor; PKA, protein kinase A; PPF, paired-pulse facilitation.

{ddagger} Present address: Institute of Neuropatholgy, University of Bonn, D-53012 Bonn, Germany.

|| To whom correspondence should be addressed. E-mail: erk5{at}columbia.edu.

© 2005 by The National Academy of Sciences of the USA


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