Presynaptic Potentiation Research Articles

Mitogen-activated protein kinase dependent presynaptic potentiation in the lateral habenula mediates depressive-like behaviors in rats.

Emerging evidence suggests that the enhanced activity of lateral habenula (LHb) is involved in depressive disorders. This abnormal potentiation of LHb neurons was shown to originate from presynaptic alterations; however, the mechanisms underlying this presynaptic enhancement and physiological consequences are yet to be elucidated. Previously, we reported that presynaptic transmission in the LHb is temporally rhythmic, showing greater activity in the afternoon than in the morning. Here, we used a learned helpless rodent model of depression to show that exposure to a stressor or incubation with the stress hormone, corticosterone, abolished the presynaptic temporal variation in the LHb. In addition, selective inhibition of mitogen-activated protein kinase (MAPK) kinase (MAPKK, MEK) activity in the LHb restored the presynaptic alteration even after stress exposure. Moreover, we observed a slight increase in phosphorylated synapsin I after stress exposure. Finally, we found that a blockade of MAPK signaling before stress exposure successfully prevented the depression-like behaviors, including behavioral despair and helplessness, in an acute learned helpless animal model of depression. Our study delineates the cellular and molecular mechanisms responsible for the abnormal presynaptic enhancement of the LHb in depression, which may mediate depressive behaviors.

HCN channel-dependent presynaptic potentiation at LA-BA synapses is required for fear memory formation

Previously, we demonstrated that auditory fear conditioning produces presynaptic potentiation at lateral to basal amygdala (LA-BA) synapses, which occludes high-frequency stimulation (HFS)-induced ex-vivo LTP. We also found that the HFS-induced ex-vivo LTP requires presynaptic hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity. In this study, we investigated whether HCN channels are necessary for auditory fear conditioning in vivo. Our results show that ZD7288, an HCN channel blocker, reduced synaptic transmission and decreased the paired pulse ratio (PPR) only in slices from rats that underwent auditory fear conditioning, but not from naïve rats. This indicates that fear conditioning involves HCN channel-dependent presynaptic potentiation at LA-BA synapses. Importantly, injecting ZD7288 into the basal amygdala (BA) before auditory fear conditioning significantly impaired long-term fear memory formation. Since HCN channel activity is necessary for LTP at LA-BA synapses but not at cortico-BA, cortico-LA, or thalamo-LA synapses, HCN channel-dependent presynaptic potentiation at LA-BA synapses appears to be crucial for auditory fear conditioning.

Mechanistic insights into cAMP-mediated presynaptic potentiation at hippocampal mossy fiber synapses.

Presynaptic plasticity is an activity-dependent change in the neurotransmitter release and plays a key role in dynamic modulation of synaptic strength. Particularly, presynaptic potentiation mediated by cyclic adenosine monophosphate (cAMP) is widely seen across the animals and thought to contribute to learning and memory. Hippocampal mossy fiber-CA3 pyramidal cell synapses have been used as a model because of robust presynaptic potentiation in short- and long-term forms. Moreover, direct presynaptic recordings from large mossy fiber terminals allow one to dissect the potentiation mechanisms. Recently, super-resolution microscopy and flash-and-freeze electron microscopy have revealed the localizations of release site molecules and synaptic vesicles during the potentiation at a nanoscale, identifying the molecular mechanisms of the potentiation. Incorporating these growing knowledges, we try to present plausible mechanisms underlying the cAMP-mediated presynaptic potentiation.

Presynaptic HCN channel activity is required for the expression of long-term potentiation at lateral amygdala to basal amygdala synapses

Recently, we reported that auditory fear conditioning leads to the presynaptic potentiation at lateral amygdala to basal amygdala (LA-BA) synapses that shares the mechanism with high-frequency stimulation (HFS)-induced long-term potentiation (LTP) ex vivo. In the present study, we further examined the molecular mechanisms underlying the HFS-induced presynaptic LTP. We found that a presynaptic elevation of Ca2+ was required for the LTP induction. Interestingly, the blockade of presynaptic but not postsynaptic HCN channels with ZD7288 completely abolished LTP induction. While ZD7288 did not alter basal synaptic transmission, the blocker fully reversed previously established LTP, indicating that HCN channels are also required for the maintenance of LTP. Indeed, HCN3 and HCN4 channels were preferentially localized in the presynaptic boutons of LA afferents. Furthermore, an inhibition of either GABAB receptors or GIRK channels eliminated the inhibitory effect of HCN blockade on the LTP induction. Collectively, we suggest that activation of presynaptic HCN channels may counteract membrane hyperpolarization during tetanic stimulation, and thereby contributes to the presynaptic LTP at LA-BA synapses.

Visualizing Presynaptic Active Zones and Synaptic Vesicles.

The presynaptic active zone (AZ) of chemical synapses is a highly dynamic compartment where synaptic vesicle fusion and neurotransmitter release take place. During evolution the AZ was optimized for speed, accuracy, and reliability of chemical synaptic transmission in combination with miniaturization and plasticity. Single-molecule localization microscopy (SMLM) offers nanometer spatial resolution as well as information about copy number, localization, and orientation of proteins of interest in AZs. This type of imaging allows quantifications of activity dependent AZ reorganizations, e.g., in the context of presynaptic homeostatic potentiation. In combination with high-pressure freezing and optogenetic or electrical stimulation AZs can be imaged with millisecond temporal resolution during synaptic activity. Therefore SMLM allows the determination of key parameters in the complex spatial environment of AZs, necessary for next generation simulations of chemical synapses with realistic protein arrangements.

CAMP-Dependent Synaptic Plasticity at the Hippocampal Mossy Fiber Terminal.

Cyclic adenosine monophosphate (cAMP) is a crucial second messenger involved in both pre- and postsynaptic plasticity in many neuronal types across species. In the hippocampal mossy fiber (MF) synapse, cAMP mediates presynaptic long-term potentiation and depression. The main cAMP-dependent signaling pathway linked to MF synaptic plasticity acts via the activation of the protein kinase A (PKA) molecular cascade. Accordingly, various downstream putative synaptic PKA target proteins have been linked to cAMP-dependent MF synaptic plasticity, such as synapsin, rabphilin, synaptotagmin-12, RIM1a, tomosyn, and P/Q-type calcium channels. Regulating the expression of some of these proteins alters synaptic release probability and calcium channel clustering, resulting in short- and long-term changes to synaptic efficacy. However, despite decades of research, the exact molecular mechanisms by which cAMP and PKA exert their influences in MF terminals remain largely unknown. Here, we review current knowledge of different cAMP catalysts and potential downstream PKA-dependent molecular cascades, in addition to non-canonical cAMP-dependent but PKA-independent cascades, which might serve as alternative, compensatory or competing pathways to the canonical PKA cascade. Since several other central synapses share a similar form of presynaptic plasticity with the MF, a better description of the molecular mechanisms governing MF plasticity could be key to understanding the relationship between the transcriptional and computational levels across brain regions.

Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.

Auditory fear conditioning facilitates neurotransmitter release at lateral amygdala to basal amygdala synapses

The lateral amygdala (LA) is a main sensory input site from the cortical and thalamic regions. In turn, LA glutamatergic pyramidal neurons strongly project to the basal amygdala (BA). Although it is well known that auditory fear conditioning involves synaptic potentiation in the LA, it is not clear whether the LA-BA synaptic transmission is modified upon auditory fear conditioning. Here we found that high-frequency stimulation ex vivo resulted in long-term potentiation (LTP) with a concomitant enhancement of neurotransmitter release at LA-BA synapses. Auditory fear conditioning also led to the presynaptic facilitation at LA-BA synapses. Meanwhile, AMPA/NMDA current ratio was not changed upon fear conditioning, excluding the involvement of postsynaptic mechanism. Notably, fear conditioning occluded electrically induced ex vivo LTP in the LA-BA pathway, indicating that the conditioning and electrically induced LTP share common mechanisms. Our findings suggest that the presynaptic potentiation of LA-BA synapses may be involved in fear conditioning.

The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity.

Synaptic vesicle (SV) release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell-intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of SV fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation.

Recruitment of release sites underlies chemical presynaptic potentiation at hippocampal mossy fiber boutons.

Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of presynaptic potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed 2-photon imaging of the genetically encoded glutamate sensor iGluu that revealed an increase in the surface area used for glutamate release at potentiated terminals. Time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between P/Q-type calcium channels and release sites mapped by Munc13-1 cluster position. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons: Synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements might enable long-term increase in synaptic strength.

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in both a plaque-dependent and -independent manner, and interact with APP and Aβ. Concurrent with elevated levels of SV-associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. A record of this paper's transparent peer review process is included in the Supplemental Information.

SynaptoPAC, an optogenetic tool for induction of presynaptic plasticity.

Optogenetic manipulations have transformed neuroscience in recent years. While sophisticated tools now exist for controlling the firing patterns of neurons, it remains challenging to optogenetically define the plasticity state of individual synapses. A variety of synapses in the mammalian brain express presynaptic long-term potentiation (LTP) upon elevation of presynaptic cyclic adenosine monophosphate (cAMP), but the molecular expression mechanisms as well as the impact of presynaptic LTP on network activity and behavior are not fully understood. In order to establish optogenetic control of presynaptic cAMP levels and thereby presynaptic potentiation, we developed synaptoPAC, a presynaptically targeted version of the photoactivated adenylyl cyclase bPAC. In cultures of hippocampal granule cells of Wistar rats, activation of synaptoPAC with blue light increased action potential-evoked transmission, an effect not seen in hippocampal cultures of non-granule cells. In acute brain slices of C57BL/6N mice, synaptoPAC activation immediately triggered a strong presynaptic potentiation at mossy fiber synapses in CA3, but not at Schaffer collateral synapses in CA1. Following light-triggered potentiation, mossy fiber transmission decreased within 20min, but remained enhanced still after 30min. The optogenetic potentiation altered the short-term plasticity dynamics of release, reminiscent of presynaptic LTP. Our work establishes synaptoPAC as an optogenetic tool that enables acute light-controlled potentiation of transmitter release at specific synapses in the brain, facilitating studies of the role of presynaptic potentiation in network function and animal behavior in an unprecedented manner. Read the Editorial Highlight for this article on page 270.

Amyloid beta 42 oligomers induce neuronal and synaptic receptor dysfunctions.

Amyloid beta 42 oligomers induce neuronal and synaptic receptor dysfunctions.

Structural Remodeling of Active Zones Is Associated with Synaptic Homeostasis.

Perturbations to postsynaptic glutamate receptors (GluRs) trigger retrograde signaling to precisely increase presynaptic neurotransmitter release, maintaining stable levels of synaptic strength, a process referred to as homeostatic regulation. However, the structural change of homeostatic regulation remains poorly defined. At wild-type Drosophila neuromuscular junction synapse, there is one Bruchpilot (Brp) ring detected by superresolution microscopy at active zones (AZs). In the present study, we report multiple Brp rings (i.e., multiple T-bars seen by electron microscopy) at AZs of both male and female larvae when GluRs are reduced. At GluRIIC-deficient neuromuscular junctions, quantal size was reduced but quantal content was increased, indicative of homeostatic presynaptic potentiation. Consistently, multiple Brp rings at AZs were observed in the two classic synaptic homeostasis models (i.e., GluRIIA mutant and pharmacological blockade of GluRIIA activity). Furthermore, postsynaptic overexpression of the cell adhesion protein Neuroligin 1 partially rescued multiple Brp rings phenotype. Our study thus supports that the formation of multiple Brp rings at AZs might be a structural basis for synaptic homeostasis.SIGNIFICANCE STATEMENT Synaptic homeostasis is a conserved fundamental mechanism to maintain efficient neurotransmission of neural networks. Active zones (AZs) are characterized by an electron-dense cytomatrix, which is largely composed of Bruchpilot (Brp) at the Drosophila neuromuscular junction synapses. It is not clear how the structure of AZs changes during homeostatic regulation. To address this question, we examined the structure of AZs by superresolution microscopy and electron microscopy during homeostatic regulation. Our results reveal multiple Brp rings at AZs of glutamate receptor-deficient neuromuscular junction synapses compared with single Brp ring at AZs in wild type (WT). We further show that Neuroligin 1-mediated retrograde signaling regulates multiple Brp ring formation at glutamate receptor-deficient synapses. This study thus reveals a regulatory mechanism for synaptic homeostasis.

2042-P: Genetic Dissection of Leptin Signaling in AgRP Neurons

Leptin, a hormone produced in white adipose tissue, acts in the brain to maintain body weight and blood glucose stability. Dysregulation of leptin or its receptor (LEPR) results in severe obesity and diabetes. Although intensive studies on leptin have transformed obesity and diabetes research, clinical applications of the molecule are still limited, at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. In our previous findings, we found that the hypothalamic AgRP(agouti-related peptide) neurons are the primary target for leptin to regulate both energy balance and glucose homeostasis. We show that CRISPR-mediated deletion of leptin receptor in AgRP neurons causes severe obesity and diabetes. We also uncover divergent mechanisms of acute and chronic inhibition of AgRP neurons by leptin (presynaptic potentiation of GABA (γ-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels (Katp), respectively). However, the molecular signaling involved in leptin's regulation on Katp and GABA transmission are not clear. In current study, we employed the CRISPR technology, combined with electrophysiology to further identify that the Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway plays an important role in mediating leptin's action on GABA transmission. We also tested that leptin can directly activate KATP channel and by using two-photon excitation microscopy, we proved that this activation is modulated by ATP/ADP ratio. Disclosure J. Xu: None. C. Chien: None. X. Yi: None. C. Bartolome: None. D. Kong: Board Member; Spouse/Partner; Jersey Biosciences Inc. Board Member; Self; PRECIDIAG INC. Funding American Diabetes Association (1-19-PDF-159-R to J.X.)

Genetic identification of leptin neural circuits in energy and glucose homeostases.

Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure, and maintain blood glucose stability1,2. Dysregulations of leptin or its receptors (LepR) result in severe obesity and diabetes3–5. Although intensive studies on leptin have transformed obesity and diabetes research2,6, clinical applications of the molecule are still limited7 which, at least in part, is due to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons expressing agouti-related peptide (AgRP) and proopiomelanocortin (POMC) were posited as the first-order leptin-responsive neurons. Selective deletion of LepR in these neurons with Cre-loxP system, however, failed to or marginally recapitulated obesity and diabetes in LepR-deficient Leprdb/db mice, suggesting that AgRP or POMC neurons are not directly required8–10. The primary neural targets for leptin are thus still unclear. Here, we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin (STZ)-induced diabetic mice and exploit CRISPR/Cas9-mediated genetic ablation of LepR in vivo. Unexpectedly, we find that AgRP neurons but not POMC neurons integrate the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AgRP neurons, and their chemogenetic inhibition reverses both diabetic hyperphagia and hyperglycemia. In sharp contrast with prior studies, we show that CRISPR-mediated deletion of LepR in AgRP neurons causes severe obesity and diabetes, fatefully replicating the phenotype of Leprdb/db mice. We also uncover divergent mechanisms underlying leptin’s acute and chronic inhibition of AgRP neurons (i.e., presynaptic potentiation of GABAergic neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings provide the framework underlying the neurobiological mechanisms of leptin and associated metabolic disorders.

Exo- and Endocytosis at a Retinal Inhibitory Synapse during Crossover Inhibition

The AII amacrine cell (AII) receives chemical and electrical synapses from rod bipolar cells (BC) and ON cone BCs. AIIs form glycinergic synapses at lobular varicosities near the soma, providing inhibitory output to the OFF pathway; this is called crossover inhibition. We performed whole-cell voltage clamp recordings and used the “sine + DC” method to make measurements of membrane capacitance (Cm) with high temporal resolution. With this approach we were able to investigate the cell membrane dynamics of this inhibitory synapse. AIIs were held at −80 mV and L-type Ca2+ currents were evoked with a 100 ms, 70 mV depolarizing step, triggering Ca2+ dependent vesicle fusion (exocytosis). Our observed Cm jumps ranged from 14.81-152.3 fF, corresponding to the fusion of 370-3800 vesicles (n=38). Presynaptic potentiation was also seen at this synapse after 4 minutes of treatment of 1 mM cAMP (n=22). Following a 50 ms depolarizing step, we saw a gradual decay in Cm, indicative of vesicular membrane retrieval (endocytosis). Tau ranged from 3.90 to 7.11 s (n=10), suggesting that AIIs are suited for fast membrane recovery. We propose that the variability in membrane dynamics of these interneurons is due to their diverse cell-to-cell lobular morphologies. In order to test this hypothesis, we performed Cm recordings in conjunction with wide-field optical sectioning of dye filled AIIs. We were able to compare Cm jumps to 3D reconstructions of the lobular varicosities from individual AIIs. Our results show that the magnitude of glycine release positively correlates to the number and overall size of these lobules (n=10). These results suggest that AIIs with larger lobules have more active zones and make more synaptic connections with OFF BCs and/or ganglion cells.

Presynaptic Ethanol Actions: Potential Roles in Ethanol Seeking.

Ethanol produces intoxication through actions on numerous molecular and cellular targets. Adaptations involving these and other targets contribute to chronic drug actions that underlie continued and problematic drinking. Among the mechanisms involved in these ethanol actions are alterations in presynaptic mechanisms of synaptic transmission, including presynaptic protein function and excitation-secretion coupling. At synapses in the central nervous system (CNS), excitation-secretion coupling involves ion channel activation followed by vesicle fusion and neurotransmitter release. These mechanisms are altered by presynaptic neurotransmitter receptors and prominently by G protein-coupled receptors (GPCRs). Studies over the last 20-25years have revealed that acute ethanol exposure alters neurotransmitter secretion, with especially robust effects on synapses that use the neurotransmitter gamma-aminobutyric acid (GABA). Intracellular signaling pathways involving second messengers such as cyclic AMP and calcium are implicated in these acute ethanol actions. Ethanol-induced release of neuropeptides and small molecule neurotransmitters that act on presynaptic GPCRs also contribute to presynaptic potentiation at synapses in the amygdala and hippocampus and inhibition of GABA release in the striatum. Prolonged exposure to ethanol alters neurotransmitter release at many CNS GABAergic and glutamatergic synapses, and changes in GPCR function are implicated in many of these neuroadaptations. These presynaptic neuroadaptations appear to involve compensation for acute drug effects at some synapses, but "allostatic" effects that result in long-term resetting of synaptic efficacy occur at others. Current investigations are determining how presynaptic neuroadaptations contribute to behavioral changes at different stages of alcohol drinking, with increasing focus on circuit adaptations underlying these behaviors. This chapter will discuss the acute and chronic presynaptic effects of ethanol in the CNS, as well as some of the consequences of these effects in amygdala and corticostriatal circuits that are related to excessive seeking/drinking and ethanol abuse.

Early postnatal exposure to lithium in vitro induces changes in AMPAR mEPSCs and vesicular recycling at hippocampal glutamatergic synapses.

Lithium is an effective mood stabilizer but its use is associated with many side effects. Electrophysiological recordings of miniature excitatory postsynaptic currents (mEPSCs) mediated by glutamate receptor AMPA-subtype (AMPARs) in hippocampal pyramidal neurons revealed that CLi (therapeutic concentration of 1 mM lithium, from days in vitro 4-10) decreased the mean amplitude and mean rectification index (RI) of AMPAR mEPSCs. Lowered mean RI indicate that contribution of Ca2+ -permeable AMPARs in synaptic events is higher in CLi neurons (supported by experiments sensitive to Ca2+ -permeable AMPAR modulation). Co-inhibiting PKA, GSK-3 beta and glutamate reuptake was necessary to bring about changes in AMPAR mEPSCs similar to that seen in CLi neurons. FM1-43 experiments revealed that recycling pool size was affected in CLi cultures. Results from minimum loading, chlorpromazine treatment and hyperosmotic treatment experiments indicate that endocytosis in CLi is affected while not much difference is seen in modes of exocytosis. CLi cultures did not show the high KCl associated presynaptic potentiation observed in control cultures. This study, by calling attention to long-term lithium-exposure-induced synaptic changes, might have implications in understanding the side effects such as CNS complications occurring in perinatally exposed babies and cognitive dulling seen in patients on lithium treatment.

Multiple forms of metaplasticity at a single hippocampal synapse during late postnatal development

Metaplasticity refers to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Numerous forms of developmental metaplasticity are observed at Schaffer collateral synapses in the rat hippocampus at the end of the third postnatal week. Emergence of spatial learning and memory at this developmental stage suggests possible involvement of metaplasticity in the final maturation of the hippocampus. Three distinct metaplastic phenomena are apparent. (1) As transmitter release probability increases with increasing age, presynaptic potentiation is reduced. (2) Alterations in the composition and channel conductance properties of AMPARs facilitate the induction of postsynaptic potentiation with increasing age. (3) Low frequency stimulation inhibits subsequent induction of potentiation in animals older but not younger than 3 weeks of age. Thus, many forms of plasticity expressed at SC-CA1 synapses are different in rats younger and older than 3 weeks of age, illustrating the complex orchestration of physiological modifications that underlie the maturation of hippocampal excitatory synaptic transmission. This review paper describes three late postnatal modifications to synaptic plasticity induction in the hippocampus and attempts to relate these metaplastic changes to developmental alterations in hippocampal network activity and the maturation of contextual learning.