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RIM1α is required for presynaptic long-term potentiation

Abstract

Two main forms of long-term potentiation (LTP)—a prominent model for the cellular mechanism of learning and memory—have been distinguished in the mammalian brain1. One requires activation of postsynaptic NMDA (N-methyl d-aspartate) receptors, whereas the other, called mossy fibre LTP, has a principal presynaptic component. Mossy fibre LTP is expressed in hippocampal mossy fibre synapses1,2, cerebellar parallel fibre synapses3,4 and corticothalamic synapses5, where it apparently operates by a mechanism that requires activation of protein kinase A. Thus, presynaptic substrates of protein kinase A are probably essential in mediating this form of long-term synaptic plasticity. Studies of knockout mice have shown that the synaptic vesicle protein Rab3A is required for mossy fibre LTP6, but the protein kinase A substrates rabphilin, synapsin I and synapsin II are dispensable7,8. Here we report that mossy fibre LTP in the hippocampus and the cerebellum is abolished in mice lacking RIM1α, an active zone protein that binds to Rab3A and that is also a protein kinase A substrate9,10. Our results indicate that the long-term increase in neurotransmitter release during mossy fibre LTP may be mediated by a unitary mechanism that involves the GTP-dependent interaction of Rab3A with RIM1α at the interface of synaptic vesicles and the active zone.

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Figure 1: Short-term plasticity and forskolin-induced potentiation at hippocampal mossy fibre synapses in RIM1α knockout and wild-type mice.
Figure 2: Mossy fibre LTP is abolished in RIM1α knockout mice.
Figure 3: Mossy fibre LTD is enhanced in RIM1α knockout mice.
Figure 4: Paired-pulse facilitation and LTP at cerebellar parallel fibre synapses in wild-type and RIM1α knockout mice.

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Acknowledgements

We thank H. Riedesel for help with the RIM1α knockout mice. This study was supported by grants from the NIH (R.C.M.).

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Castillo, P., Schoch, S., Schmitz, F. et al. RIM1α is required for presynaptic long-term potentiation. Nature 415, 327–330 (2002). https://doi.org/10.1038/415327a

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