Role In Long-term Potentiation Research Articles

Glutamatergic metabolites are associated with visual plasticity in humans

Long-term potentiation (LTP) is a basic cellular mechanism underlying learning and memory. LTP-like plasticity in the visual cortex can be induced by high frequency visual stimulation in rodents and humans. Since glutamate plays a fundamental role in LTP, this study investigated if visual cortical glutamate and glutamine levels, measured by proton magnetic resonance spectroscopy (MRS), relate to visual plasticity in humans. Since plasticity requires a delicate excitation and inhibition balance, GABA was also explored. Eighteen healthy participants completed MRS and a visual fMRI paradigm. Results revealed enhanced fMRI activations after high frequency visual stimulation, suggesting visual plasticity occurred. Higher activations were associated with higher resting glutamine levels after family wise error-correction. Exploratory analyses revealed that higher resting glutamate and GABA levels were associated with visual plasticity, suggesting there may be a critical excitation-inhibition balance necessary for experience dependent plasticity. This is the first empirical evidence that resting glutamine levels and potentially glutamate and GABA levels are associated with visual plasticity in humans.

Effects of varenicline on motor cortical plasticity in non-smokers with schizophrenia

BackgroundNicotinic acetylcholine receptors (nAChR) have been implicated in the pathophysiology of schizophrenia, and deficits in this system may contribute to high rates of cigarette smoking in this population. nAChR stimulation may modulate neuroplasticity, or long-term potentiation (LTP), which is a key mediator of cognitive performance. Varenicline is a nAChR partial agonist that may improve cognitive deficits in both smokers and non-smokers with schizophrenia; however, the mechanism by which varenicline alters cognition in schizophrenia remains unclear. Thus, the aim of this randomized, double-blind, placebo-controlled, crossover study was to determine the effects of varenicline on LTP-like plasticity indexed through transcranial magnetic stimulation (TMS) in non-smokers with schizophrenia. MethodsVarenicline (0.5mg BID × 5 doses) or placebo was administered to 9 non-smokers with schizophrenia and 10 non-smoker healthy subjects. LTP-like plasticity was induced by TMS and paired associative stimulation (PAS) at 0.1Hz to the left motor cortex and measured every 15min for two hours post-PAS. ResultsThere was a significant diagnosis × medication interaction on peak potentiation (F (3, 34)=6.04, p<0.02) and post-hoc analyses indicated that varenicline significantly increased LTP in schizophrenia and decreased LTP in healthy subjects. ConclusionsThese preliminary findings suggest that varenicline may produce differential effects in non-smoking schizophrenia compared to control subjects. Given the role of LTP in learning and memory, these observations may suggest the potential for varenicline in the treatment of cognitive deficits in patients with schizophrenia.

Interplay of enzymatic and structural functions of CaMKII in long-term potentiation.

Since the discovery of long-term potentiation (LTP) about a half-century ago, Ca2+ /CaM-dependent protein kinase II (CaMKII) has been one of the most extensively studied components of the molecular machinery that regulate plasticity. This unique dodecameric kinase complex plays pivotal roles in LTP by phosphorylating substrates through elaborate regulatory mechanisms, and is known to be both necessary and sufficient for LTP. In addition to acting as a kinase, CaMKII has been postulated to have structural roles because of its extraordinary abundance and diverse interacting partners. It now is becoming clear that these two functions of CaMKII cooperate closely for the induction of both functional and structural synaptic plasticity of dendritic spines. Because of its extraordinary abundance within neuronal cells, calmodulin kinase CaMKII has been believed to act as a structural protein as well as an enzyme during synaptic plasticity. In this review, we summarized studies in CaMKII field and provide an insight into how enzymatic and structural functions of CaMKII cooperate with each other for long-term potentiation (LTP) in neurons. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".

Ketamine Metabolites Enantioselectively Decrease Intracellular D-Serine Concentrations in PC-12 Cells.

D-Serine is an endogenous NMDA receptor co-agonist that activates synaptic NMDA receptors modulating neuronal networks in the cerebral cortex and plays a key role in long-term potentiation of synaptic transmission. D-serine is associated with NMDA receptor neurotoxicity and neurodegeneration and elevated D-serine concentrations have been associated with Alzheimer’s and Parkinsons’ diseases and amyotrophic lateral sclerosis. Previous studies have demonstrated that the ketamine metabolites (rac)-dehydronorketamine and (2S,6S)-hydroxynorketamine decrease intracellular D-serine concentrations in a concentration dependent manner in PC-12 cells. In the current study, PC-12 cells were incubated with a series of ketamine metabolites and the IC50 values associated with attenuated intracellular D-serine concentrations were determined. The results demonstrate that structural and stereochemical features of the studied compounds contribute to the magnitude of the inhibitory effect with (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine displaying the most potent inhibition with IC50 values of 0.18 ± 0.04 nM and 0.68 ± 0.09 nM. The data was utilized to construct a preliminary 3D-QSAR/pharmacophore model for use in the design of new and more efficient modulators of D-serine.

The 10,000-Fold-Effect-Retrograde Neurotransmission-a Newer Concept for Paraplegia's Physiological Revival-use of Intrathecal Sodium Nitroprusside in 100 Cases-A Priliminary Report

Background Methylprednisolone has shown level-1-benefit (20%) in traumatic paraplegia cases (but within-8hrs) yet disproved by many studies. Patients wait long for physiological recovery. Intrathecal-Sodium-Nitroprusside (ITSNP) has been used in literature to relieve vasospasm-due-to-subarachnoid-hemorrhage. ITSNP has been studied here for physiological recovery in paraplegia cases of various etiologies in a wide-window-period-range. Two mechanisms for acute-cases and one-mechanism for chronic-cases, which are interrelated, are being proposed for physiological recovery. (a) Retrograde-Neurotransmission (acute-cases). 1. During Normal excitatory impulse: at synaptic-level, glutamate activates NMDA-receptors, having Nitric-Oxide-Synthetase(NOS) on postsynaptic-membrane, for further propagation by calcium-calmodulin-complex. Nitric-Oxide (NO produced by NOS) travels backward across chemical synapse, binding to axon terminal (NO-receptor/sGC) of presynaptic-neuron, regulating-Anterograde-Neurotransmission (ANT) called Retrograde-Neurotransmission (RNT). The-haem is the ligand binding site of NO receptor/sGC. The affinity of haem exhibits 10,000-fold excess for NO than Oxygen (THE=10,000-FOLD effect) completes in 20msec. 2. In Pathological conditions: normal-ANT, synaptic-activity including-RNT is-absent. NO-donor(SNP) release NO from NOS at postsynaptic-region. NO travels backward across a chemical-synapse to bind to the haem of NO-receptor at axon-terminal of a presynaptic-neuron, generates-impulse, as in normal-condition. (b) Vasospasm (acute-cases). Perforators show vasospastic activity. NO vasodilates the perforators by NO cAMP pathway. (c) Long Term Potentiation (LTP) (chronic-cases). NO–cGMP-pathway plays a role in LTP at many synapses throughout the CNS, and at neuromuscular junction. The LTP has been reviewed both generally and with respect to specific brain regions for memory/learning. LTP plays an important factor for relief from paraplegia in chronic cases. Aims/Study Design: Principle of “generation-of-impulses from presynaptic-region to postsynaptic-region by-RNT, vasodilatation of arteriolar-perforators and LTP is the basis-of-authors” hypothesis to treat-acute-and-chronic-paraplegia-cases. Case-control-prospective-study. Material/Methods: 200 paraplegia patients {100 patients taken as control (50 with no superfusion and 50 with dextrose 5% superfusion) and 100 patients taken as in ITSNP-group} were studied here. The mean time for superfusion was 14.11 days. ITSNP administered at a dosage of 0.2 mg/kg bo wt at L3/4 level by 24 G LP needle. Pre and post ITSNP was monitored by SSEP/MEP. Results AFTER-2-HOURS in ITSNP-group MEAN-CHANGE-FROM-BASELINE-ASIA MOTOR/SENSORY-SCORE 13.84%/13.10%, after-24 hours MOTOR-1.27-points decrease(3.77%) and SENSORY 10.5 points-increase(6.22%)as compared with Control-group no-change noted upto 24 hours, At-7days ITSNP motor/sensory;11.56%/6.22% as compared with Control-group 7.60/4.48%, At-2months in ITSNP 27.69%/6.22% as compared with Control-group 16.02/4.5%. SSEP/MEP-documented-improvements-noted. Conclusions ITSNP, a-swift-acting-drug in treatment-of-paraplegia, is effective within-two-hours (mean-change-MOTOR-13.84%andSENSORY-13.10%) on-mean14.11th postparaplegia-day with a small-detrimental-response after-24 hours which-recovers-fast

Roles of protein synthesis inhibitors in long-term potentiation and depotentiation in hippocampal CA1 region of adult rats

To study the roles of protein synthesis inhibitors in long-term potentiation(LTP) and depotentiation(DP) in hippocampal CA1 region of adult rats. Standard extracellular recording technique was used to record field EPSP(fEPSP) evoked by Schaffer collateral stimulation from the CA1 subfield of adult rat hippocampal slices. Paired-pulse low-frequency stimulation(PP-LFS) or high-intensity paired-pulse low-frequency stimulation(HI-PP-LFS) was delivered to induce depotentiation 2 h after LTP induction induced by six theta-burst stimulations. Protein synthesis inhibitors were applied before and after LTP induction to study their roles in LTP and DP in hippocampal CA1 region of adult rats. When HI-PP-LFS was applied at 2 h after LTP induction, the depotentiation was induced. The mean fEPSP slopes reduced from 346.2%±26.3% to 207.1%±21.6%. This depotentiation was named as partial LTP depotentiation and maintained at least for 30 min. The percentage of depotentiation was 59.81%. Application of protein synthesis inhibitors, anisomycin and cycloheximide prior to tetanus resulted in smaller LTP compared to control group, and almost complete depotentiation was induced by HI-PP-LFS. With application of protein synthesis inhibitors anisomycin and cycloheximide 90 min after LTP induction, HI-PP-LFS still induced partial LTP depotentiation. However, there was no significant difference in the percentage of depotentiation between this group and control group. HI-PP-LFS partially reverses late phase LTP. When protein synthesis inhibitors are applied prior to tetanus, LTP amplitude is markedly reduced, and HI-PP-LFS completely reverses late-phase LTP. Application of protein synthesis inhibitors after LTP induction does not significantly affect either the amplitude or depotentiation of LTP.

Long-term potentiation and the role of N-methyl-d-aspartate receptors

N-methyl-d-aspartate receptors (NMDARs) are known for their role in the induction of long-term potentiation (LTP). Here we start by reviewing the early evidence for their role in LTP at CA1 synapses in the hippocampus. We then discuss more recent evidence that NMDAR dependent synaptic plasticity at these synapses can be separated into mechanistically distinct components. An initial phase of the synaptic potentiation, which is generally termed short-term potentiation (STP), decays in an activity-dependent manner and comprises two components that differ in their kinetics and NMDAR subtype dependence. The faster component involves activation of GluN2A and GluN2B subunits whereas the slower component involves activation of GluN2B and GluN2D subunits. The stable phase of potentiation, commonly referred to as LTP, requires activation of primarily triheteromeric NMDARs containing both GluN2A and GluN2B subunits. In new work, we compare STP with a rebound potentiation (RP) that is induced by NMDA application and conclude that they are different phenomena. We also report that NMDAR dependent long-term depression (NMDAR-LTD) is sensitive to a glycine site NMDAR antagonist. We conclude that NMDARs are not synonymous for either LTP or memory. Whilst important for the induction of LTP at many synapses in the CNS, not all forms of LTP require the activation of NMDARs. Furthermore, NMDARs mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission. It is, therefore, not possible to equate NMDARs with LTP though they are intimately linked.This article is part of a Special Issue entitled SI: Brain and Memory.

Cellular origin and regulation of D- and L-serine in in vitro and in vivo models of cerebral ischemia.

D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-serine from L-serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-serine remain elusive. The D-/L-serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-serine is derived from neurons, while L-serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.

Glutamate and Vivian Teichberg: a story about science, medicine, memory and love.

Glutamate is a fascinating molecule, and an extremely important one, due to its numerous effects in the body. Glutamate has many different faces, some unveiled and pretty well known and understood, and some still mysterious and keep attracting numerous scientists, clinicians, pharmacologists and drug designers from all over the world for dozens of years. Glutamate is the most important and abundant excitatory Neurotransmitter in the vertebrate nervous system. It plays a key role in long-term potentiation, in learning and memory and in many more neuronal functions. As such, Glutamate is involved in most aspects of the normal brain function, and in the development of the Central Nervous System (CNS). But the function of Glutamate extends beyond the CNS, as it also plays a signaling role in peripheral organs and tissues among them the heart, kidney, intestine, lungs, muscles, liver, ovary, testis, bone and pancreas and also in the adrenal, pituitary and pineal glands. Furthermore, Glutamate also induces direct and potent effects on most if not all cells of the immune system, as shown by a large body of evidence that accumulated in recent years. Due to these effects, we recently proposed to ‘upgrade’ Glutamate and recall it a ‘NeuroImmunotransmitter’ instead of a ‘Neurotransmitter’, since Glutamate seems to be very important for the ongoing function of the immune system, not only for that of the nervous system. This topic is discussed in the last part of this issue, which is devoted to Glutamate and its receptors in the immune system. People often confuse Glutamate and Glutamic acid, so it may be useful to remind the readers of the relationship between the two, and here is a brief explanation: when the amino acid Glutamic acid which is acidic (and alike each amino acid, contains a central carbon atom, to which four different groups are bonded) loses a hydrogen from its side chain, it becomes Glutamate, with a side chain composed of CH2CH2COO . In the human body, Glutamic acid almost always exists as Glutamate, because the conditions in the body favor the loss of the hydrogen atom from Glutamic acid, and it is Glutamate that is the Neurotransmitter that plays such a key role in the nervous system, in the immune system and in other body systems. Interestingly, Glutamate is a striking example of how the mere concentration of a physiological molecule, and also the length of time it is ‘seen’ by target cells that are sensitive to it, dictate whether it induces beneficial and essential activity of the target cells and tissues, or rather very detrimental effects that finally sentences them to death. Thus, Glutamate in normal, physiological and regulated concentration induces beneficial effects that are absolutely essential for the ongoing function of the brain and of several peripheral organs. Yet, when Glutamate is Editorial for the special issue on Glutamate in the Journal of Neural Transmission, in memory of Prof. Vivian Teichberg.

Mechanisms of cAMP-induced sustained activation of extracellular signal-regulated kinase in the hippocampus

Protein phosphorylation is known to regulate synaptic plasticity and memory. Protein kinases including protein kinase A and extracellular signal-regulated kinase (ERK) play important roles in these processes. Forskolin, a protein kinase A activator, induces long-term potentiation (LTP) in the hippocampus. Forskolin also induces ERK activation, which plays important roles in LTP. However, the mechanisms of forskolin-induced ERK activation are not clearly understood. Here we show that forskolin induces sustained ERK activation in the hippocampal slices. Further, blockade of protein synthesis or transcription inhibits forskolin-induced sustained ERK activation. In contrast, forskolin-induced immediate ERK activation is unaffected by inhibition of protein synthesis or transcription. Sustained ERK activation may contribute to forskolin-induced LTP in the hippocampus.

Bodily self and immune self: is there a link?

Bodily self and immune self: is there a link?

Protein kinase A regulates the long-term potentiation of intrinsic excitability in neonatal trigeminal motoneurons

Although much is known about neuronal plasticity in the mammalian hippocampus and other cortical neurons, the subcellular mechanisms underlying plasticity at the level of motor pools are less well characterized. Protein kinase A (PKA) activation plays an essential role in long-term potentiation of intrinsic excitability (LTP-IE) in layer V (LV) visual cortical neurons and may be involved in other systems as well. Trigeminal motoneurons (TMNs) participate in rhythmical motor behaviors, such as suckling, chewing, and swallowing. Using the whole-cell patch clamp method and various kinase inhibitors and activators, we investigated the mechanism of LTP-IE in neonatal rat TMNs. Ca2+ depletion using ACSF with 0mM Ca2+ or the Ca2+ chelator bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) blocked the long-lasting increase in intrinsic excitability in TMNs, showing that intracellular Ca2+ during the induction protocol is necessary for the induction of LTP-IE. We next used specific inhibitors of PKA, protein kinase C, and calcium/calmodulin-dependent protein kinase II during the induction protocol. Only the PKA inhibitor H-89 blocked the increase in the firing rate induced by the induction protocol. In addition, forskolin, which activates PKA, induced a long-lasting increase in excitability that resembled the excitability produced by the induction protocol. Thus, we conclude that LTP-IE in TMNs is calcium-dependent, and PKA is the primary regulator of this process.

The role of γ-secretase in hippocampal synaptic transmission and activity-dependent synaptic plasticity

γ-Secretase plays an important role in the generation of amyloid beta and the activation of Notch receptors. In the hope that the reduction of amyloid production can help to battle Alzheimer's disease (AD) secretases were suggested to represent a potential therapeutic targets. However, the role of γ-secretase in cellular mechanisms of memory formation under physiological conditions remained to be clarified. To this end, γ-secretase was inhibited by bath-application of DAPT or Compound E and the effects on activity-dependent hippocampal synaptic plasticity and basal synaptic transmission in acute hippocampal slices from Wistar rats were examined. Bath application of DAPT or Compound E over the whole recording period of field excitatory postsynaptic potential (fEPSP) caused a reduction of synaptic potentiation within 1h after 3×1s 100Hz/10min stimulation (HFS) of Schaffer-collateral CA1 synapses. Notably, DAPT and Compound E inhibited effectively long-term potentiation (LTP) of fEPSPs when it was applied after HFS, but not if applied only during the tetanization paradigm. Compounds did not affect basal synaptic transmission, paired-pulse facilitation and NMDA mediated fEPSPs. Our data thus imply that γ-secretase plays a role in LTP and most notably for the persistence of activity dependent synaptic plasticity, presumably through the reduction of endogenous amyloid beta and/or Notch receptor activation. Targeting of γ-secretase to prevent the onset of AD might by itself alter memory formation.

Interactions between αCaMKII and calmodulin in living cells: conformational changes arising from CaM -dependent and -independent relationships

BackgroundαCaMKII plays central and essential roles in long-term potentiation (LTP), learning and memory. αCaMKII is activated via binding with Ca2+/CaM in response to elevated Ca2+ concentration. Furthermore, prolonged increase in Ca2+ concentration leads to the auto-phosphorylation of αCaMKII at T286, maintaining the activation of αCaMKII even after Ca2+/CaM dissociation. Importantly, the active form of αCaMKII is thought to exhibit conformational change. In order to elucidate the relationships between the interaction of αCaMKII with CaM and the conformational change of αCaMKII, we generated molecular probes (YFP-αCaMKII with CFP-CaM and YFP-αCaMKII-CFP) and performed time-lapse imaging of the interaction with CaM and the conformational change, respectively, in living cells using FRET.ResultsThe interaction of YFP-αCaMKII with CFP-CaM and the conformational change of YFP-αCaMKII-CFP were induced simultaneously in response to increased concentrations of Ca2+. Consistent with previous predictions, high levels of Ca2+ signaling maintained the conformational change of YFP-αCaMKII-CFP at the time when CFP-CaM was released from YFP-αCaMKII. These observations indicated the transfer of αCaMKII conformational change from CaM-dependence to CaM-independence. Furthermore, analyses using αCaMKII mutants showed that phosphorylation at T286 and T305/306 played positive and negative roles, respectively, during in vivo interaction with CaM and further suggested that CaM-dependent and CaM-independent conformational changed forms displays similar but distinct structures.ConclusionsImportantly, these structual differences between CaM-dependent and -independent forms of αCaMKII may exhibit differential functions for αCaMKII, such as interactions with other molecules required for LTP and memory. Our molecular probes could thus be used to identify therapeutic targets for cognitive disorders that are associated with the misregulation of αCaMKII.

Decoding the Substrate Supply to Human Neuronal Nitric Oxide Synthase

Nitric oxide, produced by the neuronal nitric oxide synthase (nNOS) from L-arginine is an important second messenger molecule in the central nervous system: It influences the synthesis and release of neurotransmitters and plays an important role in long-term potentiation, long-term depression and neuroendocrine secretion. However, under certain pathological conditions such as Alzheimer’s or Parkinson’s disease, stroke and multiple sclerosis, excessive NO production can lead to tissue damage. It is thus desirable to control NO production in these situations. So far, little is known about the substrate supply to human nNOS as a determinant of its activity. Measuring bioactive NO via cGMP formation in reporter cells, we demonstrate here that nNOS in both, human A673 neuroepithelioma and TGW-nu-I neuroblastoma cells can be fast and efficiently nourished by extracellular arginine that enters the cells via membrane transporters (pool I that is freely exchangeable with the extracellular space). When this pool was depleted, NO synthesis was partially sustained by intracellular arginine sources not freely exchangeable with the extracellular space (pool II). Protein breakdown made up by far the largest part of pool II in both cell types. In contrast, citrulline to arginine conversion maintained NO synthesis only in TGW-nu-I neuroblastoma, but not A673 neuroepithelioma cells. Histidine mimicked the effect of protease inhibitors causing an almost complete nNOS inhibition in cells incubated additionally in lysine that depletes the exchangeable arginine pool. Our results identify new ways to modulate nNOS activity by modifying its substrate supply.

Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).

For more than 50 years, ketamine has proven to be a safe anesthetic drug with potent analgesic properties. The active enantiomer is S(+)-ketamine. Ketamine is mostly metabolized in norketamine, an active metabolite. During "dissociative anesthesia", sensory inputs may reach cortical receiving areas, but fail to be perceived in some association areas. Ketamine also enhances the descending inhibiting serotoninergic pathway and exerts antidepressive effects. Analgesic effects persist for plasma concentrations ten times lower than hypnotic concentrations. Activation of the (N-Methyl-D-Aspartate [NMDA]) receptor plays a fundamental role in long-term potentiation but also in hyperalgesia and opioid-induced hyperalgesia. The antagonism of NMDA receptor is responsible for ketamine's more specific properties. Ketamine decreases the "wind up" phenomenon, and the antagonism is more important if the NMDA channel has been previously opened by the glutamate binding ("use dependence"). Experimentally, ketamine may promote neuronal apoptotic lesions but, in usual clinical practice, it does not induce neurotoxicity. The consequences of high doses, repeatedly administered, are not known. Cognitive disturbances are frequent in chronic users of ketamine, as well as frontal white matter abnormalities. Animal studies suggest that neurodegeneration is a potential long-term risk of anesthetics in neonatal and young pediatric patients.

Treatment of trauma with lithium to forestall the development of posttraumatic stress disorder by pharmacological induction of a mild transient amnesia

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder that develops after exposure to trauma. Symptoms include persistent reexperiencing, persistent avoidance, persistent numbing, and persistent hyperarousal. Subsequent to trauma exposure, the onset of symptoms of an acute stress reaction can typically develop over varying amounts of time from days to months. Current pharmacotherapies for PTSD are available after symptoms manifest, and primarily consist of selective serotonin reuptake inhibitor (SSRI) antidepressants. There are currently no FDA approved pharmacological interventions available for the treatment of acutely traumatized individuals to forestall the development of PTSD after trauma and prior to the onset of symptoms.A prominent model of PTSD developed by Roger Pitman attributes the pathogenesis of PTSD to over-consolidated traumatic memories that are mediated by endogenous stress hormones released with trauma and after trauma.The molecular processes of memory consolidation in neurons are mediated by intracellular signaling pathways. One secondary messenger signaling pathway with a putative role in long-term potentiation (LTP) is the inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) secondary messenger system.Lithium, a treatment for bipolar disorder, and a pharmacotherapy that is associated with inducing transient impairments in cognition, memory, and learning, is an inhibitor of inositol monophosphatase (IMP), an enzyme in the IP3 and DAG secondary messenger pathway.I am advancing the hypothesis that the administration of lithium for a brief interval to traumatized individuals at risk for PTSD within the time period after trauma and prior to the onset of symptoms could potentially forestall the development of PTSD by disrupting LTP. I am proposing that this treatment will reduce the incidence of PTSD and reduce the severity of symptoms in those who eventually develop PTSD.

LTP Requires a Unique Postsynaptic SNARE Fusion Machinery

Membrane fusion during exocytosis is mediated by assemblies of SNARE (soluble NSF-attachment protein receptor) and SM (Sec1/Munc18-like) proteins. The SNARE/SM proteins involved in vesicle fusion during neurotransmitter release are well understood, whereas little is known about the protein machinery that mediates activity-dependent AMPA receptor (AMPAR) exocytosis during long-term potentiation (LTP). Using direct measurements of LTP in acute hippocampal slices and an in vitro LTP model of stimulated AMPAR exocytosis, we demonstrate that the Q-SNARE proteins syntaxin-3 and SNAP-47 are required for regulated AMPAR exocytosis during LTP but not for constitutive basal AMPAR exocytosis. In contrast, the R-SNARE protein synaptobrevin-2/VAMP2 contributes to both regulated and constitutive AMPAR exocytosis. Both the central complexin-binding and the N-terminal Munc18-binding sites of syntaxin-3 are essential for its postsynaptic role in LTP. Thus, postsynaptic exocytosis of AMPARs during LTP is mediated by a unique fusion machinery that is distinct from that used during presynaptic neurotransmitter release.

Prkcz null mice show normal learning and memory

Protein kinase M ζ (PKMζ) is a constitutively active form of atypical PKC that is exclusively expressed in the brain and implicated in the maintenance of long-term memory1–9. Most studies that support a role for PKMζ in memory maintenance have used pharmacological PKMζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here, we used a genetic approach and targeted exon 9 of the Prkcz gene to generate mice that lack both protein kinase C ζ (PKCζ) and PKMζ (Prkcz−/− mice). Prkcz−/− mice showed normal behavior in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behavior. Surprisingly, they did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference (CPP) for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens (NAc) reduced expression of cocaine CPP in Prkcz−/− mice. In vitro, ZIP and scrambled ZIP inhibited PKMζ, PKCι and PKCζ with similar Ki values. Chelerythrine was a weak inhibitor of PKMζ (Ki = 76 µM). Our findings show that absence of PKMζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKMζ is not present.

Regulation of hippocampus‐dependent memory by the zinc finger protein Zbtb20 in mature CA1 neurons

The mammalian hippocampus harbours neural circuitry that is crucial for associative learning and memory. The mechanisms that underlie the development and regulation of this complex circuitry are not fully understood. Our previous study established an essential role for the zinc finger protein Zbtb20 in the specification of CA1 field identity in the developing hippocampus. Here, we show that conditionally deleting Zbtb20 specifically in mature CA1 pyramidal neurons impaired hippocampus-dependent memory formation, without affecting hippocampal architecture or the survival, identity and basal excitatory synaptic activity of CA1 pyramidal neurons. We demonstrate that mature CA1-specific Zbtb20 knockout mice exhibited reductions in long-term potentiation (LTP) and NMDA receptor (NMDAR)-mediated excitatory post-synaptic currents. Furthermore, we show that activity-induced phosphorylation of ERK and CREB is impaired in the hippocampal CA1 of Zbtb20 mutant mice. Collectively, these results indicate that Zbtb20 in mature CA1 plays an important role in LTP and memory by regulating NMDAR activity, and activation of ERK and CREB.