RIM function in short- and long-term synaptic plasticity

RIM1alpha (Rab3-interacting molecule 1alpha) is a large multidomain protein that is localized to presynaptic active zones [Wang, Okamoto, Schmitz, Hofmann and Südhof (1997) Nature (London) 388, 593-598] and is the founding member of the RIM protein family that also includes RIM2alpha, 2beta, 2gamma, 3gamma and 4gamma [Wang and Südhof (2003) Genomics 81, 126-137]. In presynaptic nerve termini, RIM1alpha interacts with a series of presynaptic proteins, including the synaptic vesicle GTPase Rab3 and the active zone proteins Munc13, liprins and ELKS (a protein rich in glutamate, leucine, lysine and serine). Mouse KOs (knockouts) revealed that, in different types of synapses, RIM1alpha is essential for different forms of synaptic plasticity. In CA1-region Schaffer-collateral excitatory synapses and in GABAergic synapses (where GABA is gamma-aminobutyric acid), RIM1alpha is required for maintaining normal neurotransmitter release and short-term synaptic plasticity. In contrast, in excitatory CA3-region mossy fibre synapses and cerebellar parallel fibre synapses, RIM1alpha is necessary for presynaptic long-term, but not short-term, synaptic plasticity. In these synapses, the function of RIM1alpha in presynaptic long-term plasticity depends, at least in part, on phosphorylation of RIM1alpha at a single site, suggesting that RIM1alpha constitutes a 'phosphoswitch' that determines synaptic strength. However, in spite of the progress in understanding RIM1alpha function, the mechanisms by which RIM1alpha acts remain unknown. For example, how does phosphorylation regulate RIM1alpha, what is the relationship of the function of RIM1alpha in basic release to synaptic plasticity and what is the physiological significance of different forms of RIM-dependent plasticity? Moreover, the roles of other RIM isoforms are unclear. Addressing these important questions will contribute to our view of how neurotransmitter release is regulated at the presynaptic active zone.