Nucleotides and Phosphorylation Bi-directionally Modulate Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Binding to the N-Methyl-d-aspartate (NMDA) Receptor Subunit GluN2B

The Ca²⁺/calmodulin (CaM)-dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor are key regulators of synaptic plasticity underlying learning and memory. Direct binding of CaMKII to the NMDA receptor subunit GluN2B (formerly known as NR2B) (i) is induced by Ca²⁺/CaM but outlasts this initial Ca²⁺-stimulus, (ii) mediates CaMKII translocation to synapses, and (iii) regulates synaptic strength. CaMKII binds to GluN2B around S1303, the major CaMKII phosphorylation site on GluN2B. We show here that a phospho-mimetic S1303D mutation inhibited CaM-induced CaMKII binding to GluN2B in vitro, presenting a conundrum how binding can occur within cells, where high ATP concentration should promote S1303 phosphorylation. Surprisingly, addition of ATP actually enhanced the binding. Mutational analysis revealed that this positive net effect was caused by four modulatory effects of ATP, two positive (direct nucleotide binding and CaMKII T286 autophosphorylation) and two negative (GluN2B S1303 phosphorylation and CaMKII T305/6 autophosphorylation). Imaging showed positive regulation by nucleotide binding also within transfected HEK cells and neurons. In fact, nucleotide binding was a requirement for efficient CaMKII interaction with GluN2B in cells, while T286 autophosphorylation was not. Kinetic considerations support a model in which positive regulation by nucleotide binding and T286 autophosphorylation occurs faster than negative modulation by GluN2B S1303 and CaMKII T305/6 phosphorylation, allowing efficient CaMKII binding to GluN2B despite the inhibitory effects of the two slower reactions.     

Fast Decay of CaMKII FRET Sensor Signal in Spines after LTP Induction Is Not Due to Its Dephosphorylation

Because CaMKII is the critical Ca²⁺ sensor that triggers long-term potentiation (LTP), understanding its activation and deactivation is important. A major advance has been the development of a FRET indicator of the conformational state of CaMKII called Camui. Experiments using Camui have demonstrated that the open (active) conformation increases during LTP induction and then decays in tens of seconds, with the major fast component decaying with a time-constant of ~ 6 sec (tau1). Because this decay is faster if autophosphorylation of T286 is prevented (the autophosphorylation prolongs activity by making the enzyme active even after Ca²⁺ falls), it seemed likely that the fast decay is due to the T286 dephosphorylation. To test this interpretation, we studied the effect of phosphatase inhibitors on the single-spine Camui signal evoked by two-photon glutamate uncaging. We applied inhibitors of PP1 and PP2A, two phosphatases that are present at synapses and that have been shown to dephosphorylate CaMKII in vitro. The inhibitors increased the basal Camui activation state, indicating their effectiveness in cells. However, in no case did we find that tau1 was prolonged, contrary to what would be expected if the decay was phosphatase-dependent. This could either mean that decay was due to some unknown phosphatase or that the decay was not due to dephosphorylation. To distinguish between these possibilities, we expressed pseudo-phosphorylated Camui (T286D) (plus additional mutations [T/A] that prevented inhibitory 305/306 phosphorylation). This form had an elevated basal activation state, but was further activated during glutamate uncaging; importantly the activation state decayed with tau1 nearly the same as that of WT Camui. Therefore, the data strongly indicate that tau1 is not due to T286 dephosphorylation. We conclude that, although Camui is an excellent tool for observing CaMKII signaling, further experimentation is needed to determine how CaMKII is turned off by its dephosphorylation.     

On the Mechanism of Synaptic Depression Induced by CaMKIIN,an Endogenous Inhibitor of CaMKII

Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca²⁺ signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. Overall, our results support a direct effect of CN peptides on synaptic CaMKII-NMDAR binding and suggest that CaMKIINα,β could be critical plasticity-related proteins that may operate as cell-wide homeostatic regulators preventing saturation of LTP mechanisms or may selectively erase LTP-induced traces in specific groups of synapses.     

Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice

Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice. Nefiracetam also restored hippocampal LTP injured in OBX mice. Nefiracetam treatment restored LTP-induced PKCα (Ser657) and NR1 (Ser896) phosphorylation as well as increase in their basal phosphorylation in the hippocampal CA1 region of OBX mice. Likewise, nefiracetam improved LTP-induced CaMKIIα (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCα (Ser657) and CaMKIIα (Thr286) autophosphorylation by nefiracetam was inhibited by treatment with (±)-α-Methyl-(4-carboxyphenyl)glycine and DL-2-Amino-5-phosphonovaleric acid, respectively. The enhancement of LTP induced by nefiracetam is inhibited by treatment with 2-methyl-6-(phenylethynyl)-pyridine, but not by treatment with LY367385, suggesting that metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement. Taken together, nefiracetam ameliorates OBX-induced deficits in memory-related behaviors and impairment of LTP in the hippocampal CA1 region through activation of NMDAR and mGluR5, thereby leading to an increase in activities of CaMKIIα (Thr286) and PKCα (Ser657), respectively.     

Wip1 phosphatase modulates both long-term potentiation and long-term depression through the dephosphorylation of CaMKII

Synaptic plasticity is an important mechanism that underlies learning and cognition. Protein phosphorylation by kinases and dephosphorylation by phosphatases play critical roles in the activity-dependent alteration of synaptic plasticity. In this study, we report that Wip1, a protein phosphatase, is essential for long-term potentiation (LTP) and long-term depression (LTD) processes. Wip1-deletion suppresses LTP and enhances LTD in the hippocampus CA1 area. Wip1 deficiency-induced aberrant elevation of CaMKII T286/287 and T305 phosphorylation underlies these dysfunctions. Moreover, we showed that Wip1 modulates CaMKII dephosphorylation. Wip1^?/? mice exhibit abnormal GluR1 membrane expression, which could be reversed by the application of a CaMKII inhibitor, indicating that Wip1/CaMKII signaling is crucial for synaptic plasticity. Together, our results demonstrate that Wip1 phosphatase plays a vital role in regulating hippocampal synaptic plasticity by modulating the phosphorylation of CaMKII.     

Regulation of phosphorylation at the postsynaptic density during different activity states of Ca/calmodulin-dependent protein kinase II

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), the most abundant kinase at the postsynaptic density (PSD), is expected to be involved in activity-induced regulation of synaptic properties. CaMKII is activated when it binds calmodulin in the presence of Ca²⁺ and, once autophosphorylated on T-286/7, remains active in the absence of Ca²⁺ (autonomous form). In the present study we used a quantitative mass spectrometric strategy (iTRAQ) to identify sites on PSD components phosphorylated upon CaMKII activation. Phosphorylation in isolated PSDs was monitored under conditions where CaMKII is: (1) mostly inactive (basal state), (2) active in the presence of Ca²⁺, and (3) active in the absence of Ca²⁺. The quantification strategy was validated through confirmation of previously described autophosphorylation characteristics of CaMKII. The effectiveness of phosphorylation of major PSD components by the activated CaMKII in the presence and absence of Ca²⁺ varied. Most notably, autonomous activity in the absence of Ca²⁺ was more effective in the phosphorylation of three residues on SynGAP. Several PSD scaffold proteins were phosphorylated upon activation of CaMKII. The strategy adopted allowed the identification, for the first time, of CaMKII-regulated sites on SAPAPs and Shanks, including three conserved serine residues near the C-termini of SAPAP1, SAPAP2, and SAPAP3. Involvement of CaMKII in the phosphorylation of PSD scaffold proteins suggests a role in activity-induced structural re-organization of the PSD.     

Translocation of CaMKII to dendritic microtubules supports the plasticity of local synapses

The processing of excitatory synaptic inputs involves compartmentalized dendritic Ca²⁺ oscillations. The downstream signaling evoked by these local Ca²⁺ transients and their impact on local synaptic development and remodeling are unknown. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is an important decoder of Ca²⁺ signals and mediator of synaptic plasticity. In addition to its known accumulation at spines, we observed with live imaging the dynamic recruitment of CaMKII to dendritic subdomains adjacent to activated synapses in cultured hippocampal neurons. This localized and transient enrichment of CaMKII to dendritic sites coincided spatially and temporally with dendritic Ca²⁺ transients. We show that it involved an interaction with microtubular elements, required activation of the kinase, and led to localized dendritic CaMKII autophosphorylation. This process was accompanied by the adjacent remodeling of spines and synaptic AMPA receptor insertion. Replacement of endogenous CaMKII with a mutant that cannot translocate within dendrites lessened this activity-dependent synaptic plasticity. Thus, CaMKII could decode compartmental dendritic Ca²⁺ transients to support remodeling of local synapses.     

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.     

CaMKII Binding to GluN2B Is Differentially Affected by Macromolecular Crowding Reagents

Binding of the Ca²⁺/calmodulin(CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B controls long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning and memory. Regulation of this interaction is well-studied biochemically, but not under conditions that mimic the macromolecular crowding found within cells. Notably, previous molecular crowding experiments with lysozyme indicated an effect on the CaMKII holoenzyme conformation. Here, we found that the effect of molecular crowding on Ca²⁺/CaM-induced CaMKII binding to immobilized GluN2B in vitro depended on the specific crowding reagent. While binding was reduced by lysozyme, it was enhanced by BSA. The ATP content in the BSA preparation caused CaMKII autophosphorylation at T286 during the binding reaction; however, enhanced binding was also observed when autophosphorylation was blocked. Importantly, the positive regulation by nucleotide and BSA (as well as other macromolecular crowding reagents) did not alleviate the requirement for CaMKII stimulation to induce GluN2B binding. The differential effect of lysozyme (14 kDa) and BSA (66 kDa) was not due to size difference, as both dextran-10 and dextran-70 enhanced binding. By contrast, crowding with immunoglobulin G (IgG) reduced binding. Notably, lysozyme and IgG but not BSA directly bound to Ca²⁺/CaM in an overlay assay, suggesting a competition of lysozyme and IgG with the Ca²⁺/CaM-stimulus that induces CaMKII/GluN2B binding. However, lysozyme negatively regulated binding even when it was instead induced by CaMKII T286 phosphorylation. Alternative modes of competition would be with CaMKII or GluN2B, and the negative effects of lysozyme and IgG indeed also correlated with specific or non-specific binding to the immobilized GluN2B. Thus, the effect of any specific crowding reagent can differ, depending on its additional direct effects on CaMKII/GluN2B binding. However, the results of this study also indicate that, in principle, macromolecular crowding enhances CaMKII binding to GluN2B.     

Ionotropic glutamate receptors

In the brain, most fast excitatory synaptic transmission is mediated through L-glutamate acting on postsynaptic ionotropic glutamate receptors. These receptors are of two kinds—the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate (non-NMDA) and theN-methyl-D-aspartate (NMDA) receptors, which are thought to be colocalized onto the same postsynaptic elements. This excitatory transmission can be modulated both upward and downward, long-term potentiation (LTP) and long-term depression (LTD), respectively. Whether the expression of LTP/LTD is pre-or postsynaptically located (or both) remains an enigma. This article will focus on what postsynaptic modifications of the ionotropic glutamate receptors may possibly underly long-term potentiation/depression. It will discuss the character of LTP/LTD with respect to the temporal characteristics and to the type of changes that appears in the non-NMDA and NMDA receptor-mediated synaptic currents, and what constraints these findings put on the possible expression mechanism(s) for LTP/LTD. It will be submitted that if a modification of the glutamate receptors does underly LTP/LTD, an increase/decrease in the number of functional receptors is the most plausible alternative. This change in receptor number will have to include a coordinated change of both the non-NMDA and the NMDA receptors.     

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.     

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

Both signaling by nitric oxide (NO) and by the Ca²⁺/calmodulin (CaM)-dependent protein kinase II α isoform (CaMKIIα) are implicated in two opposing forms of synaptic plasticity underlying learning and memory, as well as in excitotoxic/ischemic neuronal cell death. For CaMKIIα, these functions specifically involve also Ca²⁺-independent autonomous activity, traditionally generated by Thr-286 autophosphorylation. Here, we demonstrate that NO-induced S-nitrosylation of CaMKIIα also directly generated autonomous activity, and that CaMKII inhibition protected from NO-induced neuronal cell death. NO induced S-nitrosylation at Cys-280/289, and mutation of either site abolished autonomy, indicating that simultaneous nitrosylation at both sites was required. Additionally, autonomy was generated only when Ca²⁺/CaM was present during NO exposure. Thus, generation of this form of CaMKIIα autonomy requires simultaneous signaling by NO and Ca²⁺. Nitrosylation also significantly reduced subsequent CaMKIIα autophosphorylation specifically at Thr-286, but not at Thr-305. A previously described reduction of CaMKII activity by S-nitrosylation at Cys-6 was also observed here, but only after prolonged (>5 min) exposure to NO donors. These results demonstrate a novel regulation of CaMKII by another second messenger system and indicate its involvement in excitotoxic neuronal cell death.     

Hydroxysafflor Yellow A Protects Neurons From Excitotoxic Death through Inhibition of NMDARs

Excessive glutamate release causes overactivation of N-methyl d-aspartate receptors (NMDARs), leading to excitatory neuronal damage in cerebral ischemia. Hydroxysafflor yellow A (HSYA), a compound extracted from Carthamus tinctorius L., has been reported to exert a neuroprotective effect in many pathological conditions, including brain ischemia. However, the underlying mechanism of HSYA''s effect on neurons remains elusive. In the present study, we conducted experiments using patch-clamp recording of mouse hippocampal slices. In addition, we performed Ca²⁺ imaging, Western blots, as well as mitochondrial-targeted circularly permuted yellow fluorescent protein transfection into cultured hippocampal neurons in order to decipher the physiological mechanism underlying HSYA''s neuroprotective effect.Through the electrophysiology experiments, we found that HSYA inhibited NMDAR-mediated excitatory postsynaptic currents without affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and γ-aminobutyric acid A-type receptor-mediated currents. This inhibitory effect of HSYA on NMDARs was concentration dependent. HSYA did not show any preferential inhibition of either N-methyl d-aspartate receptor subtype 2A- or N-methyl d-aspartate receptor subtype 2B- subunit-containing NMDARs. Additionally, HSYA exhibits a facilitatory effect on paired NMDAR-mediated excitatory postsynaptic currents. Furthermore, HSYA reduced the magnitude of NMDAR-mediated membrane depolarization currents evoked by oxygen-glucose deprivation, and suppressed oxygen-glucose deprivation–induced and NMDAR-dependent ischemic long-term potentiation, which is believed to cause severe reperfusion damage after ischemia. Through the molecular biology experiments, we found that HSYA inhibited the NMDA-induced and NMDAR-mediated intracellular Ca²⁺ concentration increase in hippocampal cultures, reduced apoptotic and necrotic cell deaths, and prevented mitochondrial damage. Together, our data demonstrate for the first time that HSYA protects hippocampal neurons from excitotoxic damage through the inhibition of NMDARs. This novel finding indicates that HSYA may be a promising pharmacological candidate for the treatment of brain ischemia.     

Catalytically Dead αCaMKII K42M Mutant Acts as a Dominant Negative in the Control of Synaptic Strength

During long-term potentiation (LTP) of excitatory synapses, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is activated by Ca²⁺ influx through NMDA receptors that potentiate AMPA receptor currents by insertion of additional GluR1-containing receptors at the synapse and by increasing AMPA channel conductance, as well as by stimulating structural changes. CaMKII is also involved in the maintenance of LTP and contributes to maintenance of behavioral sensitization by cocaine or amphetamine. Recent studies show that transient expression of catalytically dead αCaMKII K42M mutant after exposure to amphetamine persistently reverses the behavioral effects of the addiction. A suggested interpretation is that this mutant acts as a dominant negative in the control of synaptic strength, but this interpretation has not been physiologically tested. Here we investigate the effect of αCaMKII K42M mutant expressed in single CA1 pyramidal neurons on basal excitatory neurotransmission in cultured rat hippocampal organotypic slices. The mutant caused nearly 50% reduction in the basal CA3–CA1 transmission, while overexpression of the wild-type αCaMKII had no effect. This result is consistent with the dominant negative hypothesis, but there are complexities. We found that the decrease in basal transmission did not occur when activity in the slices was suppressed after transfection by TTX or when NMDA receptors were blocked by APV. Thus, the dominant negative effect requires neural activity for its expression.     

STDP in a bistable synapse model based on CaMKII and associated signaling pathways

The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch. However, it is still unclear whether experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such a network. We present a detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentration, and high calcium transients can switch the system from the weakly phosphorylated (DOWN) to the highly phosphorylated (UP) state of the CaMKII (similar to a LTP event). We show here that increased CaMKII dephosphorylation activity at intermediate Ca²⁺ concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). This can be achieved if protein phosphatase activity promoting CaMKII dephosphorylation activates at lower Ca²⁺ levels than kinase activity. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. This shows that the CaMKII protein network can account for both induction, through LTP/LTD-like transitions, and storage, due to its bistability, of synaptic changes.     

Autophosphorylation of αCaMKII affects social interactions in mice

The α‐Ca²⁺/calmodulin‐dependent protein kinase II (αCaMKII), a key regulator of the glutamatergic synapse, has been implicated in many psychiatric disorders characterized by social impairments. Here we tested whether autophosphorylation of αCaMKII at threonine 286, which prolongs the activity of the enzyme, affects social behaviors in mice. We observed that autophosphorylation‐deficient (αCaMKII‐T286A) mutant female mice showed abnormal social behaviors characterized by decreased social preference and interest in conspecifics of the same sex, as compared to their wild‐type littermates. Moreover, we developed a mathematical approach to analyze social interactions in group‐housed mice in the automated IntelliCages. Using this approach we observed that αCaMKII‐T286A mutants show decreased levels of social interactions in a social group, as compared with WT mice. WT mice increased the frequency of close social interactions when learning about the location of the food reward. This phenomenon was absent in the mutants. Overall, our data indicates that autophosphorylation of αCaMKII affects social interactions.     

The cell adhesion molecule neuroplastin-65 inhibits hippocampal long-term potentiation via a mitogen-activated protein kinase p38-dependent reduction in surface expression of GluR1-containing glutamate receptors

Neuroplastin-65 is a brain-specific, synapse-enriched member of the immunoglobulin (Ig) superfamily of cell adhesion molecules. Previous studies highlighted the importance of neuroplastin-65 for long-term potentiation (LTP), but the mechanism was unclear. Here, we show how neuroplastin-65 activation of mitogen-activated protein kinase p38 (p38MAPK) modified synapse strength by altering surface glutamate receptor expression. Organotypic hippocampal slice cultures treated with the complete extracellular fragment of neuroplastin-65 (FcIg1-3) sustained an increase in the phosphorylation of p38MAPK and an inability to induce LTP at hippocampal synapses. The LTP block was reversed by application of the p38MAPK inhibitor SB202190, suggesting that p38MAPK activation occurred downstream of neuroplastin-65 binding and upstream of the loss of LTP. Further investigation revealed that the mechanism underlying neuroplastin-65-dependent prevention of LTP was a p38MAPK-dependent acceleration of the loss of surface-exposed glutamate receptor subunits that was reversed by pretreatment with the p38MAPK inhibitor SB202190. Our results indicate that neuroplastin-65 binding and associated stimulation of p38MAPK activity are upstream of a mechanism to control surface glutamate receptor expression and thereby influence plasticity at excitatory hippocampal synapses.     

Group I mGluRs and Long-Term Depression: Potential Roles in Addiction?

Addiction is an enormous societal problem. A number of recent studies have focused on adaptations at glutamatergic synapses that may play a role in the behavioral responses to drugs of abuse. These studies have largely focused on NMDA receptor-dependent forms of synaptic plasticity such as NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD). A growing body of evidence, however, suggests that metabotropic glutamate receptors (mGluRs) also play important roles in the behavioral responses to drugs of abuse and participate in producing synaptic plasticity at glutamate synapses. In this review, we focus first on the evidence supporting a role for mGluRs in addiction and then on the properties of mGluR-dependent forms of synaptic plasticity, focusing in particular on Gq-linked receptor-induced LTD.     

Long-term potentiation in hippocampal oriens interneurons: postsynaptic induction,presynaptic expression and evaluation of candidate retrograde factors

Several types of hippocampal interneurons exhibit a form of long-term potentiation (LTP) that depends on Ca²⁺-permeable AMPA receptors and group I metabotropic glutamate receptors. Several sources of evidence point to a presynaptic locus of LTP maintenance. The retrograde factor that triggers the expression of LTP remains unidentified. Here, we show that trains of action potentials in putative oriens-lacunosum-moleculare interneurons of the mouse CA1 region can induce long-lasting potentiation of stimulus-evoked excitatory postsynaptic currents that mimics LTP elicited by high-frequency afferent stimulation. We further report that blockers of nitric oxide production or TRPV1 receptors failed to prevent LTP induction. The present results add to the evidence that retrograde signalling underlies N-methyl-d-aspartate (NMDA) receptor-independent LTP in oriens interneurons, mediated by an unidentified factor.     

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

Many endogenous factors influence the time course and extent of the detrimental effects of amyloid β-protein (Aβ) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aβ-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aβ_1–42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca²⁺-dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aβ_1–42. Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aβ_1–42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aβ was ineffective. We also examined the duration of action of Aβ, including water soluble Aβ from Alzheimer''s disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aβ dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aβ.