Morphofunctional effects of applications of glutamate and dopamine on the goldfish Mauthner neurons

In the goldfish, we studied the effects of intramedullar applications of glutamate (Glu), dopamine (DA), and of long-lasting rotational stimulation on the functional activity, dimensional characteristics, and ultrastructure of Mauthner neurons (MNs). Applications of Glu, especially when combined with rotational stimulation, were found to result in suppression of the function of MNs, in a decrease in their dimensions and lengths of desmosome-like contacts (DLCs, whose structure is determined by filamentous actin) in afferent mixed and chemical synapses, and in destruction of actin microfilaments in the cytoskeleton of MNs. Applications of DA, vice versa, induced an increase in the resistance to the effects of long-lasting stimulation and stabilized the dimensions of MNs; the length of DLCs increased in afferent synapses of both the above types, and the number of fibrillar actin bridges in the DLC cleft of mixed synapses also increased. Bundles of the actin filaments, which were preserved after stimulation, appeared in the cytoskeleton of MNs. Testing of the action of neurotransmitters on actin preparations in vitro showed that Glu entirely depolymerizes filamentous actin, while DA, vice versa, polymerizes monomeric actin. Thus, the Glu-and DA-induced reactions are similar in their types and are of a reciprocal nature both in the actin cytoskeleton of MNs in situ and in purified actin in vitro; these effects correlate with suppression of the functional state of MNs under the influence of Glu and with stabilization of this state under the influence of DA. These results agree with the concept on the roles of depolymerization and polymerization of actin in changes of the morphofunctional state of MNs and show that actin of the cytoskeleton of MNs is a cellular target for the actions of Glu and DA. The similarity between the effects of tested neurotransmitters on actin in MNs in situ and in cell-free preparations in vitro allows us to hypothesize that these transmitters can penetrate into the neuron. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 320–330, July–August, 2006.     

Ultrastructural Changes in the Mixed Synapses of Mauthner Neurons Related to Long-Term Potentiation and Natural Modification of the Motor Function

We examined changes in the ultrastructure of afferent mixed synapses on the membrane of Mauthner neurons (M cells) of the goldfish, which were related to two functional states, long-term potentiation (LTP) of the electrotonic response (a model form of the memory trace) and adaptation (resistivity to fatigue resulting from long-lasting motor training and considered a natural form of the memory trace manifested on the neuronal level). LTP was induced in medullary slices using high-frequency electrical stimulation of the afferent input. Adaptation was produced using natural vestibular stimulation (everyday motor training, which modified motor behavior of the fish and function of the M cell). It was supposed that if the LTP phenomenon is involved in the formation of natural memory, both the adaptation and the LTP states should be accompanied by similar specific structural modifications. Indeed, it was found that in both cases the number of fibrillar bridges in the gaps of desmosome-like contacts (DLC) in the mixed synapses on the M cell surface demonstrated an about twofold increase. These bridges are known to include actin filaments, which function as conductors of cationic signals; thus, the LTP-related increase in the density of bridges corresponds to increased efficacy of electrotonic coupling via mixed synapses. Such a structural correlate of LTP, which probably has the same functional significance in mixed synapses of the adapted M cells, allows us to suppose that LTP is a natural property of the nervous system. The LTP-type intensification of the relay function of mixed synapses, which corresponds to adaptation, is probably a compensatory rearrangement allowing M cells to maintain some balance of the synaptic influences and, at the same time, to remain in a stable and plastic state; this is necessary for stable functioning under changing environmental conditions.     

Coincident activity of converging pathways enables simultaneous long-term potentiation and long-term depression in hippocampal CA1 network in vivo

Memory is believed to depend on activity-dependent changes in the strength of synapses, e.g. long-term potentiation (LTP) and long-term depression (LTD), which can be determined by the sequence of coincident pre- and postsynaptic activity, respectively. It remains unclear, however, whether and how coincident activity of converging efferent pathways can enable LTP and LTD in the pathways simultaneously. Here, we report that, in pentobarbital-anesthetized rats, stimulation (600 pulses, 5 Hz) to Schaffer preceding to commissural pathway within a 40-ms timing window induced similar magnitudes of LTP in both pathways onto synapses of CA1 neurons, with varied LTP magnitudes after reversal of the stimulation sequence. In contrast, in urethane-anesthetized or freely-moving rats, the stimulation to Schaffer preceding to commissural pathway induced Schaffer LTP and commissural LTD simultaneously within a 40-ms timing window, without affecting synaptic efficacy in the reversed stimulation sequence. Coincident activity of Schaffer pathways confirmed the above findings under pentobarbital and urethane anesthesia. Thus, coincident activity of converging afferent pathways tends to switch the pathways to be LTP only or LTP/LTD depending on the activity states of the hippocampus. This network rule strengthens the view that activity-dependent synaptic plasticity may well contribute to memory process of the hippocampal network with flexibility or stability from one state to another.     

Role of long-term potentiation in mechanism of the conditioned learning

The review analyzes the fundamental problem of study of the neuronal mechanisms underlying processes of learning and memory. As a neuronal model of these phenomena there was considered one of the cellular phenomena that has characteristics similar with those in the process of “memorizing”—such as the long-term potentiation (LTP). LTP is easily reproduced in certain synapses of the central nervous system, specifically in synapses of hippocampus and amygdala. As the behavioral model of learning, there was used the conditioned learning, in frames of which production of the context-dependent/independent conditioned reaction was considered. Analysis of literature data showed that various stages of LTP produced on synapses of hippocampus or amygdala can be comparable with certain phases of the process of learning. Based on the exposed material the authors conclude that plastic changes of synapses of hippocampus and amygdala can represent the morphological substrate of some kinds of learning and memory.     

G protein-coupled receptors control NMDARs and metaplasticity in the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) are the major forms of functional synaptic plasticity observed at CA1 synapses of the hippocampus. The balance between LTP and LTD or “metaplasticity” is controlled by G-protein coupled receptors (GPCRs) whose signal pathways target the N-methyl-D-asparate (NMDA) subtype of excitatory glutamate receptor. We discuss the protein kinase signal cascades stimulated by Gαq and Gαs coupled GPCRs and describe how control of NMDAR activity shifts the threshold for the induction of LTP.     

The effect of prior prolonged low frequency stimulation on the further synaptic plasticity at hippocampal CA1 synapses

The objective of this study is to determine the role of prior prolonged low frequency stimulation (900 pulses at 1 Hz) on the further induced long-term potentiation (LTP) and depression (LTD) of synaptic activity in the rat hippocampal CA1 area. Hippocampal slices and standard extracellular field potential recording techniques were employed. LTP and LTD were induced using stimulation at 5 Hz (900 pulses) paired with or without simultaneous application of 1 microM isoproterenol respectively, at either normal CA1 synapses or CA1 synapses that were pre-conditioned with prolonged low frequency stimulation at 1 Hz. LTD could be successfully induced upon 900 pulses of stimulation given at 5 Hz at normal synapses (82.1 +/- 2.9%; n = 5); it was, however, reduced to 96.5 +/- 4.7% (n = 6) at the preconditioned synapses. When paired with application of isoproterenol, 900 pulses of stimulation given at 5 Hz produced LTP (139.9 +/- 9.6%, n = 5) at normal synapses. The magnitude of LTP is decreased to (130 +/- 13.2%) (n = 6) at pre-conditioned synapses, though the difference is not significant. These results suggest that at a given CA1 synapses the expression of LTP and LTD is dependent on their history of use.     

CaMKII T286 phosphorylation has distinct essential functions in three forms of long-term plasticity

The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear. Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation (pT286), which induces Ca²⁺-independent autonomous kinase activity. In addition, we compared the role of pT286 among three forms of long-term plasticity (NMDAR-dependent LTP and LTD, and mGluR-dependent LTD) using simultaneous live imaging of endogenous CaMKII together with synaptic marker proteins. We determined that after LTP stimuli, pT286 autophosphorylation accelerated CaMKII movement to excitatory synapses. After NMDAR-LTD stimuli, pT286 was strictly required for any movement to inhibitory synapses. Similar to NMDAR-LTD, we found the mGluR-LTD stimuli did not induce CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, we demonstrate that the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Thus, despite its prominent role in LTP, we conclude that CaMKII T286 autophosphorylation is also required for both major forms of hippocampal LTD, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.     

Molecular constraints on synaptic tagging and maintenance of long-term potentiation: a predictive model

Protein synthesis-dependent, late long-term potentiation (LTP) and depression (LTD) at glutamatergic hippocampal synapses are well characterized examples of long-term synaptic plasticity. Persistent increased activity of protein kinase M ζ (PKMζ) is thought essential for maintaining LTP. Additional spatial and temporal features that govern LTP and LTD induction are embodied in the synaptic tagging and capture (STC) and cross capture hypotheses. Only synapses that have been "tagged" by a stimulus sufficient for LTP and learning can "capture" PKMζ. A model was developed to simulate the dynamics of key molecules required for LTP and LTD. The model concisely represents relationships between tagging, capture, LTD, and LTP maintenance. The model successfully simulated LTP maintained by persistent synaptic PKMζ, STC, LTD, and cross capture, and makes testable predictions concerning the dynamics of PKMζ. The maintenance of LTP, and consequently of at least some forms of long-term memory, is predicted to require continual positive feedback in which PKMζ enhances its own synthesis only at potentiated synapses. This feedback underlies bistability in the activity of PKMζ. Second, cross capture requires the induction of LTD to induce dendritic PKMζ synthesis, although this may require tagging of a nearby synapse for LTP. The model also simulates the effects of PKMζ inhibition, and makes additional predictions for the dynamics of CaM kinases. Experiments testing the above predictions would significantly advance the understanding of memory maintenance.     

The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses

In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr⁷⁵, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 μM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release.     

Regulation of Long-Term Plasticity Induction by the Channel and C-Terminal Domains of GluN2 Subunits

Conventional long-term potentiation (LTP) and long-term depression (LTD) are induced by different patterns of synaptic stimulation, but both forms of synaptic modification require calcium influx through NMDA receptors (NMDARs). A prevailing model (the “calcium hypothesis”) suggests that high postsynaptic calcium elevation results in LTP, whereas moderate elevations give rise to LTD. Recently, additional evidence has come to suggest that differential activation of NMDAR subunits also factors in determining which type of plasticity is induced. While the growing amount of data suggest that activation of NMDARs containing specific GluN2 subunits plays an important role in the induction of plasticity, it remains less clear which subunit is tied to which form of plasticity. Additionally, it remains to be determined which properties of the subunits confer upon them the ability to differentially induce long-term plasticity. This review highlights recent studies suggesting differential roles for the subunits, as well as findings that begin to shed light on how two similar subunits may be linked to the induction of opposing forms of plasticity.     

Developmentally restricted synaptic plasticity in a songbird nucleus required for song learning

We provide evidence here of long-term synaptic plasticity in a songbird forebrain area required for song learning, the lateral magnocellular nucleus of the anterior neostriatum (LMAN). Pairing postsynaptic bursts in LMAN principal neurons with stimulation of recurrent collateral synapses had two effects: spike timing- and NMDA receptor-dependent LTP of the recurrent synapses, and LTD of thalamic afferent synapses that were stimulated out of phase with the postsynaptic bursting. Both types of plasticity were restricted to the sensory critical period for song learning, consistent with a role for each in sensory learning. The properties of the observed plasticity are appropriate to establish recurrent circuitry within LMAN that reflects the spatiotemporal pattern of thalamic afferent activity evoked by tutor song. Such circuit organization could represent a tutor song memory suitable for reinforcing particular vocal sequences during sensorimotor learning.     

alphaCaMKII Is essential for cerebellar LTD and motor learning

Activation of postsynaptic alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII) by calcium influx is a prerequisite for the induction of long-term potentiation (LTP) at most excitatory synapses in the hippocampus and cortex. Here we show that postsynaptic LTP is unaffected at parallel fiber-Purkinje cell synapses in the cerebellum of alphaCaMKII(-/-) mice. In contrast, a long-term depression (LTD) protocol resulted in only transient depression in juvenile alphaCaMKII(-/-) mutants and in robust potentiation in adult mutants. This suggests that the function of alphaCaMKII in parallel fiber-Purkinje cell plasticity is opposite to its function at excitatory hippocampal and cortical synapses. Furthermore, alphaCaMKII(-/-) mice showed impaired gain-increase adaptation of both the vestibular ocular reflex and optokinetic reflex. Since Purkinje cells are the only cells in the cerebellum that express alphaCaMKII, our data suggest that an impairment of parallel fiber LTD, while leaving LTP intact, is sufficient to disrupt this form of cerebellar learning.     

Computational model of the effects of stochastic conditioning on the induction of long-term potentiation and depression

The long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength are currently considered to be the first microscopic steps leading to learning and memory. The great majority of experiments (both in vitro and in vivo) studying the basic mechanisms of LTP and LTD induction use conditioning protocols in which the presynaptic stimuli are delivered at constant frequencies. This is not, however, what is commonly found in vivo, where a highly irregular spiking activity seems to drive most of the neuronal functions. Thus, some important aspects of the induction characteristics of LTP and LTD expressed in vivo might have been overlooked by the experiments. Using a simple schematic model for a synapse we show here that, in fact, the statistical properties of a presynaptic conditioning signal could change the probability to induce LTP and/or LTD, suggesting a new and faster operating mode for a synapse. Received: 3 September 1998 / Accepted in revised form: 14 April 1999     

Effect of Adaptation to Graduated Physical Exercises on the Function of the Rat Myocardium

On isolated hearts obtained from control rats and rats subjected to regular physical exercises (forced swimming) during 6 weeks, we studied the contractile activity of the heart, resistance of the myocardium to ischemia/reperfusion-induced injuries, as well as the dependence of the developed and end-diastolic pressures in the aortic ventricle (AV) on the strain of the myocardium (by means of a dosed increase in the volume of a polyethylene reservoir inserted into the ventricle). It was demonstrated that adaptation to regular graduated physical exercises exerts a positive effect on the functional state of the AV myocardium and its contractile function. This was manifested in intensification of the contractile activity of the myocardium, a decrease in its oxygen “job cost,” and an increase in the resistance to injuries induced by ischemia-reperfusion. In addition, regular physical trainings led to an increase in the resistance of the AV myocardium to the strain. In trained rats, the plateau of the Frank–Starling plot was significantly greater than that in control animals, while the rigidity of the AV myocardium was significantly lower. Neirofiziologiya/Neurophysiology, Vol. 41, No. 1, pp. 41–47, January–February, 2009.     

Role of AMPA receptor trafficking in NMDA receptor-dependent synaptic plasticity in the rat lateral amygdala

Stimulated exocytosis and endocytosis of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors (AMPARs) have been proposed as primary mechanisms for the expression of hippocampal CA1 long-term potentiation (LTP) and long-term depression (LTD), respectively. LTP and LTD, the two most well characterized forms of synaptic plasticity, are thought to be important for learning and memory in behaving animals. Both LTP and LTD can also be induced in the lateral amygdala (LA), a critical structure involved in fear conditioning. However, the role of AMPAR trafficking in the expression of either LTP or LTD in this structure remains unclear. In this study, we show that NMDA receptor-dependent LTP and LTD can be reliably induced at the synapses of the auditory thalamic inputs to the LA in brain slices. The expression of LTP was prevented by post-synaptic blockade of vesicle-mediated exocytosis with application of a light chain of Clostridium tetanus neurotoxin and was associated with increased cell-surface AMPAR expression. In contrast, the expression of LTD was prevented by post-synaptic application of a glutamate receptor 2-derived interference peptide, which specifically blocks the stimulated clathrin-dependent endocytosis of AMPARs, and was correlated with a reduction in plasma membrane-surface expression of AMPARs. These results strongly suggest that regulated trafficking of post-synaptic AMPARs is also involved in the expression of LTP and LTD in the LA.     

Interrelated modification of excitatory and inhibitory synaptic connections in the olivary-cerebellar neuronal network

The model of simultaneous interrelated modification in the efficacy of synaptic inputs to different neurons of the olivary-cerebellar network is developed. The model is based on the following features of the network: simultaneous activation of the input layer (granule) cells and the output layer (deep cerebellar nuclei) cells by mossy fibers; simultaneous activation of Purkinje cells and cerebellar cells of the input and output layers by climbing fibers and their collaterals; the existence of local feedback excitatory, inhibitory, and disinhibitory circuits. The rise (decrease) of posttetanic Ca2+ concentration in reference to the level produced by previous stimulation causes the decrease (increase) in cGMP-dependent protein kinase G activity, and increase (decrease) inprotein phosphatase 1 activity. Subsequent dephosphorylation (phosphorylation) of ionotropic receptors results in simultaneous LTD (LTP) of the excitatory input together with the LTP (LTD) of the inhibitory input to the same neuron. The character of interrelated modifications of synapses at different cerebellar levels strongly depends on the olivary cell activity. In the presence (absence) of the signal from the inferior olive LTD (LTP) of the output cerebellar signal can be induced.     

Interplay of the magnitude and time-course of postsynaptic Ca<Superscript>2 + </Superscript> concentration in producing spike timing-dependent plasticity

Synaptic strength can be modified by the relative timing of pre- and postsynaptic activity, a phenomenon termed spike timing-dependent plasticity (STDP). Studies of neurons in the hippocampus and in other regions have found that when presynaptic activity occurs within a narrow time window, typically 10 or 20 ms, before postsynaptic activity, long-term potentiation (LTP) is induced, while if presynaptic activity occurs within a similar time window after postsynaptic activity, long-term depression (LTD) results. The mechanisms underlying these modifications are not completely understood, although there is strong evidence that the postsynaptic Ca ^2 + concentration plays a central role. Some previous modeling of STDP has focused on the dynamics of the postsynaptic Ca ^2 + concentration, while other work has studied biophysical mechanisms of how a synapse can exist in, and switch between, different states corresponding to LTP and LTD. Building on previous work in these two areas we have developed the first low level STDP model of a tristable biochemical system that incorporates induction and maintenance of both LTP and LTD. Our model is able to explain the STDP observed in hippocampal neurons in response to pre- and postsynaptic pulse pairs, using only parameters derived from previous work and without the need for parameter fine-tuning. Our results also give insight into how and why the time course of the postsynaptic Ca ^2 + concentration can lead to either LTP or LTD, and suggest that voltage dependent calcium channels play a key role.     

Modeling of the actomyosin ATPase activity

In the rapid “quench” kientics of myosin, the “initial phosphate burst” is the excess inorganic phosphate that is produced during the early time-course of ATP hydrolysis by myosin subfragment-1 (S-1) or HMM. In general, the existence of a Pi burst implies a rapid (i.e., generally an order of magnitude faster than the steady-state hydrolysis rate) lysis of the phospho-anhydride bond within the ATP molecule, followed by one or more slower steps that are rate limiting for the process. Thus, the presence of a Pi burst can provide an important clue to the mechanism of the reaction. However, in the case of actomyosin, this clue as long been the subject of controversy and misunderstanding. To measure the (initial) Pi burst, myosin S-1 (or HMM) is rapidly mixed with ATP and then the mixture is acid quenched after a specific time period. The medium produced contains free Pi generated from hydrolysis of the ATP. The quantitative measure of the phosphate generated in this way has always been significantly greater than that expected by steady-state “release” of Pi alone, and it is that very difference between this measured Pi after the quench and that amount of Pi expected to be released by steady-state considerations in that same time period that has been referred to as the “initial Pi burst”. Recent investigations of the kinetics of Pi release have used an entirely new method that directly measures the release of Pi from the enzyme-product complex. These studies have made reference to the properties of the “initial Pi burst” in the presence of actin, as well as to a new kinetic entity: the “burst of Pi release”, and have been often vague concerning the true nature of the initial Pi burst, as well as the properties of Pi release as predicted by the current models of the actin activation of the myosin ATPase activity. The purpose of the current article is to correct this oversight, to discuss the “burst” in some detail, and to display the kinetics predicted by the current models for the actin activation of myosin. Furthermore, predictions for the kinetics of the new “burst of Pi release” are discussed in terms of its ability to discriminate between the two current competing models for actin activation of the myosin ATPase activity.     

A Voltage-Based STDP Rule Combined with Fast BCM-Like Metaplasticity Accounts for LTP and Concurrent “Heterosynaptic” LTD in the Dentate Gyrus In Vivo

Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.     

Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.At several excitatory and inhibitory synapses, neuronal activity can trigger enduring increases or decreases in neurotransmitter release, thereby producing long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength, respectively. In the last decade, many studies have revealed that these forms of plasticity are ubiquitously expressed in the mammalian brain, and accumulating evidence indicates that they may underlie behavioral adaptations occurring in vivo. These studies have also uncovered a wide range of induction mechanisms, which converge on the presynaptic terminal where an enduring modification in the neurotransmitter release process takes place. Interestingly, presynaptic forms of LTP/LTD can coexist with classical forms of postsynaptic plasticity. Such diversity expands the dynamic range and repertoire by which neurons modify their synaptic connections. This review discusses mechanistic aspects of presynaptic LTP and LTD at both excitatory and inhibitory synapses in the mammalian brain, with an emphasis on recent findings.