Molecular Psychiatry (2005) 10, 185–200 & 2005 Nature Publishing Group All rights reserved 1359-4184/05 $30.00 www.nature.com/mp FEATURE REVIEW Active zones for presynaptic plasticity in the brain P Garcı´a-Junco-Clemente1, P Linares-Clemente1 and R Ferna´ndez-Chaco´n1 Departamento de Fisiologı´aMe´dica y Biofı´sica, Facultad de Medicina, Universidad de Sevilla. Avda. Sa´nchez-Pizjua´n4, Sevilla, Spain Some of the most abundant synapses in the brain such as the synapses formed by the hippocampal mossy fibers, cerebellar parallel fibers and several types of cortical afferents express presynaptic forms of long-term potentiation (LTP), a putative cellular model for spatial, motor and fear learning. Those synapses often display presynaptic mechanisms of LTP induction, which are either NMDA receptor independent of dependent of presynaptic NMDA receptors. Recent investigations on the molecular mechanisms of neurotransmitter release modulation in short- and long-term synaptic plasticity in central synapses give a preponderant role to active zone proteins as Munc-13 and RIM1-alpha, and point toward the maturation process of synaptic vesicles prior to Ca2 þ -dependent fusion as a key regulatory step of presynaptic plasticity. Molecular Psychiatry (2005) 10, 185–200. doi:10.1038/sj.mp.4001628 Published online 4 January 2005 Keywords: synaptic plasticity; LTP; active zone; neurotransmitter release; RIM; Munc13 Introduction from hours to weeks. Long-term plasticity changes take place either as an enhancement of synaptic A remarkable property of neuronal circuits is the strength, LTP, or a reduction, long-term depression ability to change the strength of their synaptic (LTD). The long-term synaptic plasticity model more connections in response to prior activity. Synaptic intensively studied, LTP’ was initially described at the plasticity leads to the enhancement or depression of hippocampus.3 Although LTP has been virtually neural transmission efficacy and influences a number observed in every glutamatergic synapse studied in of important aspects of brain function. Paradigmati- the mammalian brain, the best studied model is the cally, synaptic plasticity is envisioned as the cellular NMDA (N-methyl-D-aspartate) receptor-dependent pillar to explain memory formation and spatial, motor LTP in the CA1 region of the hippocampus. For many and fear learning. However, changes in synaptic years, the most controversial questions regarding LTP efficacy might also participate in relevant processes have been related to the issue of whether LTP as synapse establishment during brain development induction and/or expression occurs as a pre- or post- or homeostatic maintenance of excitability to avoid synaptic phenomena. Presynaptically expressed plas- neuronal excytotoxicity. ticity generally translates into an increase or a Traditionally, classification of different types of decrease of neurotransmitter release. Postsynaptically synaptic plasticity attends to the time scale at which expressed plasticity involves changes at the number or they occur. Short-term synaptic plasticity changes the properties of postsynaptic receptors with no happen as potentiation (STP) or depression (STD) of changes in the amount of neurotransmitter release. synaptic responses, and they last from hundreds of Although it is generally accepted that the site of miliseconds to a few minutes. According to their induction and expression of NMDA-dependent LTP is duration and kinetics, short-term enhancements are basically postsynaptic, the existence of presynapti- defined as facilitation, augmentation or post-tetanic cally induced LTP based on the activation of potentiation. Short-term plasticity is generally ex- presynaptic NMDA receptors has been recently de- plained by direct presynaptic effects as residual monstrated.4 Additionally, a number of synapses have elevations of intracellular Ca2 þ concentration, for been described during the last decade where LTP enhancing changes, or depletion of some pool of turned out to be NMDA independent, being induced readily releasable vesicles, for depressing changes and expressed at the presynaptic terminals. Indeed, (reviewed Regehr and Stevens,1 and Zucker and presynaptic LTP is expressed in some of the most Regehr2). In contrast, long-term plasticity changes last abundant synapses in the brain such as the hippo- campal mossy fibers, the cerebellar parallel fiber and Correspondence: Dr R Ferna´ndez-Chaco´n, Departamento de corticothalamic terminals. The best studied example Fisiologı´aMe´dica y Biofı´sica, Facultad de Medicina, Universidad of presynaptic LTP occurs at the mossy fibers in the de Sevilla. Avda. Sa´nchez-Pizjua´n 4, Sevilla, Spain. CA3 region of the hippocampus. Excellent reviews E-mail: [email protected] Received 22 October 2004; revised 26 October 2004; accepted 10 have described general mechanisms of synaptic November 2004 plasticity and discussed the controversies of the site Presynaptic plasticity in the brain P Garcı´a-Junco-Clemente et al 186 of expression of LTP.5–9 In this review, we will action potential compared to the first.1 It is accepted describe different synaptic types displaying distinct that synapses with a low probability of release (Pr) forms of presynaptic plasticity where an enhancement normally present PPF, while synapses with a high Pr of neurotransmitter release occurs. We will then tend instead to have paired-pulse depression.1 discuss recent advances that point out putative During mossy fiber LTP, Zalutsky and Nicoll molecular targets in the synaptic vesicle cycle as observed a decrease in PPF consistent with an responsible for plastic changes in neurotransmitter elevation in Pr. In contrast, no similar changes were release, which are important for short- and long-term observed during associational-commisural LTP. synaptic potentiation. Although a number of studies supported that hypoth- esis,21–26 there are other reports indicating that the mechanism of mossy fiber LTP induction involves an Presynaptic LTP independent of NMDA receptor initial rise in postsynaptic Ca2 þ -concentration.27–30 Hippocampal mossy fibers However, the presynaptic expression of mossy fiber Based on studies of the possible role of LTP in LTP is unanimously accepted and several groups have learning and memory, it has been stated the so-called provided solid evidences supporting that view: a synaptic plasticity and memory (SPM) hypothesis: decrease in PPF during mossy fiber LTP,20,31–33 an ‘activity-dependent synaptic plasticity is induced at increase in quantal content (the number of vesicles appropriate synapses during memory formation and released during a presynaptic action potential)33 and a is both necessary and sufficient for the information significant reduction in the number of release fail- storage underlying the type of memory mediated by ures.33 Synaptic release probability can be directly the brain area in which that plasticity is observed’.10 measured as the rate of inhibition of synaptic In that sense, hippocampal LTP is probably involved responses using MK-801, an irreversible open-chan- in the initial encoding and storage of spatial memory. nel blocker of the NMDA receptor.34,35 MK-801 only There is general agreement regarding the existence of blocks irreversibly NMDA receptors that have been different types of LTP in the hippocampus.6 Nowa- opened by glutamate and, therefore, synapses that are days, many investigators accept that LTP at the CA1 activated become unavailable to subsequent stimuli. region of the hippocampus is triggered at the post- The rate of decline of the NMDA-dependent EPSCs synaptic terminals and an important mechanism of (excitatory post synaptic currents) depends on the Pr, expression resides in the trafficking and function of because a higher Pr results in a higher number of glutamate receptors of AMPA (alpha-amino-3-hydro- NMDA receptors being opened per stimulus. xy-5-methyl-4-isoxazole propionic acid) type.11,12 Although mossy fiber LTP is NMDA receptor inde- Nevertheless, a number of experiments led to propose pendent, Weisskopf and Nicoll36 showed that NMDA presynaptic mechanisms of LTP expression such as receptors are present at mossy fiber synapses and the existence of retrograde messengers able to modify used the MK-801 method to reveal that upon LTP presynaptic function.13–18 In any case, a form of induction, there is a large increase in the probability hippocampal LTP exists, which is independent of of release,37 emphasizing the presynaptic expression NMDA receptors and genuinely expressed presynap- of that type of LTP. Although most of the studies were tically at the mossy fiber pathway formed between the performed in slices, the presynaptic nature of mossy axons of granule cells of the dentate gyrus and the fiber LTP has been also shown in cultured granule pyramidal cells of area CA3.19,20 Although it is cells.38,39 generally accepted that mossy fiber LTP expression An important issue is to define the synaptic is presynaptic, there are controversies regarding mechanisms that get modified to increase neurotrans- whether the induction is pre- or post-synaptic. mitter release. Tong et al.38 using cultured granule Zalutsky and Nicoll20 took advantage of the particular cells showed that after total blockade of the evoked property of CA3 pyramidal neurons, which displays NMDAR EPSC by MK-801, the application of the LTP- LTP at two types of synaptic inputs from both the inducing tetanic stimulus resulted in the appearance associational–commisural fibers and the mossy fiber of