Regulation of hippocampal long-term potentiation and long-term depression by diacylglycerol kinase ζ

Diacylglycerol (DAG) is an important signaling molecule at neuronal synapses. Generation of synaptic DAG is triggered by the activation of diverse surface receptors including N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptors. The action of DAG is terminated by enzymatic conversion of DAG to phosphatidic acid (PA) by DAG kinases (DGKs). DGKζ, one of many mammalian DGKs, is localized to synapses through direct interaction with the postsynaptic scaffolding protein PSD-95, and regulates dendritic spine maintenance by promoting DAG-to-PA conversion. However, a role for DGKζ in the regulation of synaptic plasticity has not been explored. We report here that Schaffer collateral-CA1 pyramidal synapses in the hippocampus of DGKζ-knockout (DGKζ(-/-) ) mice show enhanced long-term potentiation (LTP) and attenuated long-term depression (LTD). The attenuated LTD at DGKζ(-/-) synapses involves both NMDA receptors and metabotropic glutamate receptors. These changes in LTP and LTD were reversed by phospholipase C inhibition, which blocks DAG production. Similar reversals in both LTP and LTD were also induced by inhibition of protein kinase C, which acts downstream of DAG. These results suggest that DGKζ regulates hippocampal LTP and LTD by promoting DAG-to-PA conversion, and establish that phospholipase C and protein kinase C lie upstream and downstream, respectively, of DGKζ-dependent regulation of hippocampal LTP and LTD.     

Blockade of BDNF signaling turns chemically‐induced long‐term potentiation into long‐term depression

Long‐term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain‐derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically‐induced long‐term potentiation (c‐LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c‐LTP by bath‐application of the N‐methyl‐d ‐aspartate receptor (NMDAR) coagonist glycine or by the K⁺ channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c‐LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin‐receptor‐kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K‐252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA‐12, abolished the c‐LTP‐induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c‐LTP, provoking a shift from a long‐term increase to a long‐term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c‐LTP‐induced plasticity in hippocampal neurons and its blockade leads to a switch of c‐LTP into chemical‐LTD (c‐LTD). © 2013 Wiley Periodicals, Inc.     

mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors

Excitatory glutamatergic synapses on dopamine (DA) neurons of the ventral tegmental area (VTA) undergo long-lasting changes during conditioning of natural rewards and in response to drug exposure. It has been suggested that the ensuing context-dependent behavioural changes are associated with an increased efficacy of synaptic afferents determined by the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the molecular nature of the forms of LTP/LTD involved remains elusive. Here, using acute rat brain slices, we describe a form of long-term depression (LTD) that was engaged by synaptic activity or exogenous agonists activating group I metabotropic glutamate receptors (mGluR) and was sensitive to mGluR1 antagonists. Prior to mGluR-LTD, AMPAR mediated excitatory postsynaptic currents (EPSCs) showed strong rectification at positive potentials and were sensitive to Joro spider toxin (JST), a selective blocker of GluR2-lacking AMPARs. After mGluR-LTD, AMPAR EPSCs had linear current-voltage relations and became insensitive to JST. We conclude that activation of mGluR1s triggers a redistribution exchanging native receptors for GluR2 containing AMPARs, ultimately causing LTD that may oppose pathological neuroadaptation.     

Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses

Hippocampal CA3 pyramidal neurons receive synaptic inputs from both mossy fibres (MFs) and associational fibres (AFs). Long-term potentiation (LTP) at these synapses differs in its induction sites and N-methyl-D-aspartate receptor (NMDAR) dependence. Most evidence favours the presynaptic and postsynaptic mechanisms for induction of MF LTP and AF LTP, respectively. This implies that molecular and functional properties differ between MF and AF synapses at both presynaptic and postsynaptic sites. In this study, we focused on the difference in the postsynaptic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) between these synapses. To trace the subunit-specific trafficking of AMPARs at each synapse, GluR1 and GluR2 subunits were introduced into CA3 pyramidal neurons in hippocampal organotypic cultures using the Sindbis viral expression system. The electrophysiologically-tagged GluR2 AMPARs, produced by the viral-mediated transfer of the unedited form of GluR2 (GluR2Q), were inserted into both MF and AF postsynaptic sites in a neuronal activity-independent manner. Endogenous Ca(2+)-impermeable AMPARs at these synapses were replaced with exogenous Ca(2+)-permeable receptors, and Ca(2+) influx via the newly expressed postsynaptic AMPARs induced NMDAR-independent LTP at AF synapses. In contrast, no GluR1 AMPAR produced by the gene transfer was constitutively incorporated into AF postsynaptic sites, and only a small amount into MF postsynaptic sites. The synaptic trafficking of GluR1 AMPARs was triggered by the activity of Ca(2+)/calmodulin-dependent kinase II or high-frequency stimulation to induce LTP at AF synapses, but not at MF synapses. These results indicate that MF and AF postsynaptic sites possess distinct properties for AMPAR trafficking in CA3 pyramidal neurons.     

Distinct trafficking and expression mechanisms underlie LTP and LTD of NMDA receptor‐mediated synaptic responses

Although an increasing number of studies have demonstrated the plasticity of NMDA receptor‐mediated synaptic transmission, little is known about the molecular mechanisms that underlie this neurologically important process. In a study of NMDAR‐mediated synaptic responses in hippocampal Schaffer‐CA1 synapses whose AMPA receptor (AMPAR) activity is totally blocked, we uncovered differences between the trafficking mechanisms that underlie the long‐term potentiation (LTP) and long‐term depression (LTD) that can be induced in these cells under these conditions. The LTP‐producing protocol failed to induce a change in the amplitude of NMDAR‐mediated postsynaptic currents (NMDAR EPSCs) in the first 5–10 min, but induced gradual enhancement of NMDAR EPSCs thereafter that soon reached a stable magnitude. This “slow” LTP of NMDAR EPSCs (LTP_NMDA) was blocked by inhibiting exocytosis or actin polymerization in postsynaptic cells. By contrast, LTD of NMDAR EPSCs (LTD_NMDA) was immediately inducible, and, although it was blocked by the actin stabilizer, it was unaffected by exocytosis or endocytosis inhibitors. Furthermore, concomitant changes in the decay time of NMDAR EPSCs suggested that differential switches in NR2 subunit composition accompanied LTP_NMDA and LTD_NMDA, and these changes were blocked by the calcium buffer BAPTA or an mGluR antagonist. Our results suggest that LTP_NMDA and LTD_NMDA utilize different NMDAR trafficking pathways and express different ratios of NMDAR subunits on the postsynaptic surface. © 2009 Wiley‐Liss, Inc.     

Induction mechanisms and modulation of bidirectional burst stimulation-induced synaptic plasticity in the hippocampus

Spike bursting is an important physiological mode of the hippocampus. Whereas the rules of spike timing-dependent synaptic plasticity are well defined for pairs of single action potentials (APs) and excitatory postsynaptic potentials (EPSPs), long-term modification of synaptic responses is much less understood for more complex pre- and postsynaptic spike patterns. We induced a burst stimulation (BS)-associated form of synaptic plasticity in rat CA1 hippocampal slices by repeatedly pairing three EPSPs with a burst of APs induced by postsynaptic current injection. In distinct groups of cells, this induction paradigm resulted in long-term potentiation (LTP), long-term depression (LTD) or no change in synaptic strength. LTP was N -methyl- d -aspartate receptor-dependent, whereas LTD could be blocked by a metabotropic glutamate receptor antagonist or inhibition of Ca²⁺ influx through voltage-activated Ca²⁺ channels. LTP was predicted by a more depolarized membrane potential and a higher initial AP frequency. LTD was facilitated by a larger time interval between the last EPSP and its preceding AP. We conclude from these findings that associative BS induces a bidirectional form of long-term synaptic plasticity that cannot be fully explained by spike timing rules. Postsynaptic membrane potential and Ca²⁺ influx further influence the sign and magnitude of synaptic modification. LTP and LTD have distinct mechanisms and can be selectively modulated. This supports the concept of two independent coincidence detectors for LTP and LTD, and extends the physiological options to modulate synaptic plasticity and maintain a putative balance between potentiation and depression in synaptic networks.     

Postnatal alterations in induction threshold and expression magnitude of long-term potentiation and long-term depression at hippocampal synapses

Activity-dependent synaptic plasticity refines neural networks during development and subserves information processing in adulthood. Previous research has revealed postnatal alterations in synaptic plasticity at nearly all forebrain synapses, suggesting different forms of synaptic plasticity may contribute to network development and information processing. To assess possible relationships between modifications in synaptic plasticity and maturation of cognitive ability, we examined excitatory synaptic function in area CA1 of the mouse hippocampus ～3 weeks of age, when hippocampal-dependent learning and memory abilities first emerge. Long-term potentiation (LTP) and depression (LTD) of synaptic efficacy were observed in slices from juvenile animals younger than 3 weeks of age. Both pre- and postsynaptic mechanisms supported LTP and LTD in juveniles. After the third postnatal week, the magnitude of LTP was reduced and the threshold for postsynaptic induction was reduced, but the threshold for presynaptic induction was increased. The reduced threshold for postsynaptic LTP appeared to be due, partly, to an increase in baseline excitatory synaptic strength, which likely permitted greater postsynaptic depolarization during induction. Low frequency stimulation did not induce LTD at this more mature stage, but it blocked subsequent induction of LTP, suggesting metaplastic differences across age groups. Late postnatal modifications in activity-dependent synaptic plasticity might reflect attenuation of mechanisms more closely tied to network formation (presynaptic potentiation and pre- and postsynaptic depression) and unmasking of mechanisms underlying information processing and storage (associative postsynaptic potentiation), which likely impact the integrative capacity of the network and regulate the emergence of adult-like cognitive abilities.     

Protein kinase Mzeta enhances excitatory synaptic transmission by increasing the number of active postsynaptic AMPA receptors

Protein kinase Mzeta (PKMzeta), a constitutively active, atypical PKC isoform, enhances synaptic strength during the maintenance of long-term potentiation (LTP). Here we examine the mechanism by which PKMzeta increases synaptic transmission. Postsynaptic perfusion of PKMzeta during whole-cell recordings of CA1 pyramidal cells strongly potentiated the amplitude of AMPA receptor (AMPAR)-mediated miniature EPSCs (mEPSCs). Nonstationary fluctuation analysis of events recorded before and after PKMzeta enhancement showed that the kinase doubled the number of functional postsynaptic AMPAR channels. After sustained potentiation, application of a PKMzeta inhibitor reversed the increase in functional channel number to basal levels, suggesting that persistent increase of PKMzeta is required to maintain the postsynaptic localization of a mobile subpopulation of receptors. The kinase did not affect other sites of LTP expression, including presynaptic transmitter release, silent synapse conversion, or AMPAR unit conductance. Thus PKMzeta functions specifically to establish and maintain long-term increases in active postsynaptic AMPAR number.     

Relations Between Long-term Synaptic Modifications and Paired-pulse Interactions in the Rat Neocortex

The phenomenon of paired-pulse facilitation (PPF) was exploited to investigate the role of presynaptic mechanisms in the induction and maintenance of long-term synaptic plasticity in the neocortex. Long-term potentiation (LTP) and depression (LTD) were induced without afferent activation by applying tetani of intracellular pulses. Our results show that synaptic modifications closely resembling LTP and LTD can be induced by postsynaptic activation alone. The polarity of these synaptic modifications depends on initial properties of the input, as indicated by a correlation between initial PPF ratio and post-tetanic amplitude changes: inputs exhibiting strong PPF, which might be associated with low release probability tend to be potentiated, while inputs with small PPF are more likely to show depression. Maintenance of both LTP and LTD involve presynaptic mechanisms, as indicated by changes in PPF ratios and in failure rate after LTP or LTD induction. Presynaptic mechanisms could include changes in release probability and/or in the number of active release sites. Because induction was postsynaptic, this supports the notion of a retrograde signal. The relative contribution of pre- and postsynaptic mechanisms in the maintenance of long-term synaptic modifications depends on the initial state of the synaptic input and on LTP magnitude. PPF changes were especially pronounced in inputs which had initially high PPF and underwent strong potentiation. Since LTP and LTD are associated with changes of PPF ratios these synaptic modifications do not only alter the gain but also the temporal properties of synaptic transmission. Because of the LTP associated reduction of PPF, potentiated inputs profit less from temporal summation, favouring transmission of synchronized, low frequency activity.     

Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses

It is commonly accepted that the hippocampus is critically involved in the explicit memory formation of mammals. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum can be classified according to their firing properties into burst-spiking and regular-spiking cells. In the present study we demonstrate that burst-spiking and regular-spiking cells show fundamentally different forms of low frequency-induced synaptic plasticity in rats. In burst-spiking cells, low-frequency stimulation (at 0.5–5 Hz) induces frequency-dependent long-term depression (LTD) with a maximum at 1 Hz. This LTD is dependent on the activation of NMDAR and masks an mGluR-dependent long-term potentiation (LTP). In contrast, in regular-spiking cells low-frequency stimulation induces an mGluR-dependent LTP that masks an NMDAR-dependent LTD. Both processes depend on postsynaptic Ca²⁺-signaling as BAPTA prevents the induction of synaptic plasticity in both cell types. Thus, mGluR-dependent LTP and NMDAR-dependent LTD occur simultaneously at CA1-subiculum synapses and the predominant direction of synaptic plasticity relies on the cell type investigated. Our data indicate a novel mechanism for the sliding-threshold model of synaptic plasticity, in which induction of LTP and LTD seems to be driven by the relative activation state of NMDAR and mGluR. Our observation that the direction of synaptic plasticity correlates with the discharge properties of the postsynaptic cell reveals a novel and intriguing mechanism of target specificity that may serve in tuning the significance of neuronal information by trafficking hippocampal output onto either subicular burst-spiking or regular-spiking cells.     

Regulation of synaptic structure and function by palmitoylated AMPA receptor binding protein

AMPA receptor binding protein (ABP) is a multi-PDZ domain scaffold that binds and stabilizes AMPA receptor (AMPAR) GluR2/3 subunits at synapses. A palmitoylated N-terminal splice variant (pABP-L) concentrates in spine heads, whereas a non-palmitoylated form (ABP-L) is intracellular. We show that postsynaptic Sindbis viral expression of pABP-L increased AMPAR mediated mEPSC amplitude and frequency and elevated surface levels of GluR1 and GluR2, suggesting an increase in AMPA receptors at individual synapses. Spines were enlarged and more numerous and nerve terminals contacting these cells displayed enlarged synaptophysin puncta. A non-palmitoylated pABP-L mutant (C11A) did not change spine density or size. Exogenous pABP-L and endogenous GRIP, a related scaffold, colocalized with NPRAP (δ-catenin), to which ABP and GRIP bind, and with cadherins, which bind NPRAP. Thus postsynaptic pABP-L induces pre and postsynaptic changes that are dependent on palmitoylation and likely achieved through ABP association with a multi-molecular cell surface signaling complex.     

Regulation of spine morphology and synaptic function by LIMK and the actin cytoskeleton

Filamentous actin (F-actin) is highly enriched in the dendritic spine, a specialized postsynaptic structure on which the great majority of the excitatory synapses are formed in the mammalian central nervous system (CNS). The protein kinases of the Lim-kinase (LIMK) family are potent regulators of actin dynamics in many cell types and they are abundantly expressed in the CNS, including the hippocampus. Using a combination of genetic manipulations and electrophysiological recordings in mice, we have demonstrated that LIMK-1 signaling is important in vivo in the regulation of the actin cytoskeleton, spine morphology, and synaptic function, including hippocampal long-term potentiation (LTP), a prominent form of long lasting synaptic plasticity thought to be critical to memory formation. Our results provide strong genetic evidence that LIMK and its substrate ADF/cofilin are involved in spine morphology and synaptic properties and are consistent with the notion that the Rho family small GTPases and the actin cytoskeleton are critical to spine structure and synaptic regulation.     

ERK1/2 but not p38 MAP kinase is essential for the long-term depression in mouse cerebellar slices

Mitogen-activated protein kinase (MAPK) cascade is essential for synaptic plasticity and learning. In the hippocampus, three different MAPK subfamilies, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK and c-Jun NH2-terminal protein kinase (JNK), selectively regulate activity-dependent glutamate receptor trafficking during long-term potentiation (LTP), long-term depression (LTD), and depotentiation after LTP, respectively. Although LTP and LTD at cerebellar parallel fibre (PF)-Purkinje cell synapses are thought to be controlled by glutamate receptor trafficking, the involvement of MAPK subfamilies has not been systemically studied in cerebellar slice preparations. To clarify the role of the MAPK cascade in cerebellar LTD, we performed biochemical and electrophysiological analyses using ICR mouse cerebellar slices. Immunoblot analyses using phosphorylation-specific antibodies for MAPKs revealed that among the three MAPKs, ERK1/2 was specifically activated by phorbol ester, which could induce LTD in cerebellar slices. In addition, U0126, a specific inhibitor of the MAPK kinase-ERK1/2 pathway, abrogated the induction of LTD in cerebellar slices, whereas SB203580 and SP600125, specific inhibitors of p38 MAPK and JNK, respectively, had no effect. Although metabotropic glutamate receptor 1 (mGluR1) has been suggested as a possible downstream target of ERK1/2 in cell-culture preparations, mGluR1-activated slow excitatory postsynaptic currents (EPSCs) were not affected by U0126 treatment in slices. These findings indicate that unlike hippocampal LTD mediated by p38 MAPK, glutamate receptor trafficking during cerebellar LTD was regulated by a distinct mechanism involving ERK1/2 in slice preparations.     

Nogo‐A controls structural plasticity at dendritic spines by rapidly modulating actin dynamics

Nogo‐A and its receptors have been shown to control synaptic plasticity, including negatively regulating long‐term potentiation (LTP) in the cortex and hippocampus at a fast time scale and restraining experience‐dependent turnover of dendritic spines over days. However, the molecular mechanisms and the precise time course mediating these actions of Nogo‐A are largely unexplored. Here we show that Nogo‐A signaling in the adult nervous system rapidly modulates the spine actin cytoskeleton within minutes to control structural plasticity at dendritic spines of CA3 pyramidal neurons. Indeed, acute Nogo‐A loss‐of‐function transiently increases F‐actin stability and results in an increase in dendritic spine density and length. In addition, Nogo‐A acutely restricts AMPAR insertion and mEPSC amplitude at hippocampal synaptic sites. These data indicate a crucial function of Nogo‐A in modulating the very tight balance between plasticity and stability of the neuronal circuitry underlying learning processes and the ability to store long‐term information in the mature CNS. © 2016 Wiley Periodicals, Inc.     

Induction of long-term depression is associated with decreased dendritic length and spine density in layers III and V of sensorimotor neocortex

Long-term potentiation (LTP) and long-term depression (LTD) are currently the most widely investigated models of the synaptic mechanisms underlying learning and memory. Previous research has shown that induction of LTP increases measures of pyramidal cell dendritic morphology in the hippocampus and layers III and V of the neocortex. However, to date there are no reports on the direct effects of LTD induction on dendritic morphology. Here, we investigated the effects of LTD induction on sensorimotor pyramidal cell dendritic morphology. Rats carried a stimulating electrode in the corpus callosum (midline) and a recording electrode in the right sensorimotor cortex. Each rat received low-frequency stimulation composed of 900 pulses at 1 Hz or handling daily for a total 15 days. Evoked potentials (EPs) of the transcallosal pathway were recorded in the right hemisphere before and after the 15 days of stimulation or handling. The rats were then perfused with saline and the brains were immediately processed for Golgi-Cox staining. Our results show that LTD induction is related to decreases in dendritic length and spine density both in layers III and V as well as a decrease in dendritic branch complexity in layer V of the sensorimotor cortex. Thus, neuronal alterations following modifications in neocortical synaptic efficacy may provide a general mechanism for the physical instantiation of learning and memory.     

Relation Between Dendritic Ca2+ Levels and the Polarity of Synaptic Long-term Modifications in Rat Visual Cortex Neurons

Long-term changes of synaptic efficacy, in particular when they are use-dependent, are candidate mechanisms for the storage of information in the nervous system. In a variety of brain structures, including the neocortex and hippocampus, synapses are susceptible to long-term potentiation (LTP) and long-term depression (LTD). It has been hypothesized that the polarity of the synaptic gain change depends on the amplitude of the postsynaptic [Ca²⁺]_i rise, the threshold for the induction of LTD being lower than that for the induction of LTP. To test this assumption, we characterized Ca²⁺ signals in layer II/III pyramidal cells of rat visual cortex slices, using the fluorescent Ca²⁺ indicator fura-2, during application of stimulation protocols that had been adjusted to reliably induce either LTP or LTD in cells not loaded with fura-2. At dendritic sites activated by the stimulated afferents the intracellular [Ca²⁺] concentration ([Ca²⁺]_i) reached higher amplitudes and decayed more slowly with stimuli inducing LTP than with those inducing LTD. To directly analyse the functional significance of the observed difference in the Ca²⁺ signal amplitude, we examined whether a tetanization protocol suitable for the induction of LTP can be converted into a protocol inducing LTD by injecting the postsynaptic cells with Ca²⁺ chelators that reduce the concentration of effective free Ca²⁺. In the presence of fura-2 or BAPTA [bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetate], the stimulation protocol that would normally produce LTP induced either LTD or failed to induce synaptic modifications altogether. These results support the hypothesis that the amplitude of the postsynaptic rise in [Ca²⁺]_i is a key factor in the determination of the polarity of synaptic gain change.     

Photochemical inactivation analysis of temporal dynamics of postsynaptic native AMPA receptors in hippocampal slices

Postsynaptic expression of AMPA-type glutamate receptors (AMPAR) is more mobile than previously thought. Much evidence suggests that AMPAR are delivered from intracellular reserved pools to postsynaptic sites in a constitutive, as well as activity-dependent manner by exocytosis, lateral diffusion, or diffusional trapping. These notions were supported by optical monitoring of AMPAR subunits labeled with macromolecular tags such as GFP or Immunobeads, although it remains uncertain whether the mode and rate of synaptic delivery are similar to native "unlabeled" receptors. To reveal the real-time dynamics of native AMPAR in situ, photochemical inactivation of surface receptors using 6-azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX), a photoreactive AMPAR blocker, was adopted for acute hippocampal slices of mice. Because of the irreversible block due to cross-link formation between ANQX and surface AMPAR, recovery of EPSPs after photoinactivation reflects the time course of synaptic delivery of intracellular AMPAR. Brief UV illumination with fast application of ANQX resulted in persistent suppression of EPSPs for a prolonged period of up to 3 h, suggesting minimal synaptic delivery of AMPAR by exocytosis in the resting condition. Kinetic analysis of EPSP recovery clarified that the supply of postsynaptic AMPAR from the intracellular pool is dominated in the initial, but not in the later, phase of long-term potentiation (LTP). These results suggest that constitutive synaptic delivery is minimal in the resting condition at intact hippocampal synapses in a time scale of hours, while postsynaptic AMPAR are replaced with those in intracellular pools almost exclusively in an activity-dependent manner, typically shortly after LTP induction.     

Calcineurin Inhibition Rescues Early Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer’s type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer’s disease.     

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen‐activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen‐activated protein kinases, extracellular‐regulated kinase is involved in the in vitro induction of long‐term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor‐dependent long‐term depression (LTD) in vitro. Although c‐Jun N‐terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c‐Jun N‐terminal protein kinase‐inhibiting peptide (D‐JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D‐JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c‐Jun, a significant enhancement of LTD and a facilitation of short‐term depression into LTD. Both LTP and short‐term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK‐dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.