Various Forms Of Synaptic Plasticity Research Articles

Membrane Insertion of New AMPA Receptors and LTP Induced by Glycine is Prevented by Blocking NR2A-Containing NMDA Receptors in the Rat Visual Cortex In Vitro

N-methyl-D-aspartate receptors (NMDA-Rs) activation has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in glycine-induced long-term potentiation (LTP) of miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A-containing and NR2B-containing NMDA-Rs in glycine-induced LTP in visual cortical slices from 13-15 day old rats. We found that glycine-induced LTP of mEPSCs was readily induced in layer II/III pyramidal neurons of the rat visual cortex with glycine. D-APV, a selective NMDA-R antagonist, blocked the glycineinduced LTP. Moreover, the selective NR2B-containing NMDA-R antagonists (Ro 25-6981) displayed no influence on the glycine-induced LTP. However, Zn2+, a voltage-independent NR2A-containing NMDA-R antagonist, prevented glycine-induced LTP. These results suggest that the glycine-induced LTP in layer II/III pyramidal neurons of the rat visual cortex is NMDA-R-dependent and requires NR2A-containing NMDA-Rs, not NR2B-containing NMDA-Rs.

Membrane Insertion of New AMPA Receptors and LTP Induced by Glycine is Prevented by Blocking NR2A-Containing NMDA Receptors in the Rat Visual Cortex In Vitro

N-methyl-D-aspartate receptors (NMDA-Rs) activation has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in glycine-induced long-term potentiation (LTP) of miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A-containing and NR2B-containing NMDA-Rs in glycine-induced LTP in visual cortical slices from 13-15 day old rats. We found that glycine-induced LTP of mEPSCs was readily induced in layer II/III pyramidal neurons of the rat visual cortex with glycine. D-APV, a selective NMDA-R antagonist, blocked the glycineinduced LTP. Moreover, the selective NR2B-containing NMDA-R antagonists (Ro 25-6981) displayed no influence on the glycine-induced LTP. However, Zn2+, a voltage-independent NR2A-containing NMDA-R antagonist, prevented glycine-induced LTP. These results suggest that the glycine-induced LTP in layer II/III pyramidal neurons of the rat visual cortex is NMDA-R-dependent and requires NR2A-containing NMDA-Rs, not NR2B-containing NMDA-Rs.

Constitutive internalization and recycling of metabotropic glutamate receptor 5 (mGluR5)

Ligand-dependent and ligand-independent endocytic trafficking of G-protein coupled receptors (GPCRs) is critical for accurate receptor-mediated signaling and its regulation. Metabotropic glutamate receptor 5 (mGluR5) is a GPCR that plays a crucial role in circuit formation in the brain and also in various forms of synaptic plasticity including learning and memory. Outside the central nervous system this receptor also plays very important role in various other non-neuronal cells like heart cells, skin cells, hepatocytes, etc. Although the ligand-mediated endocytosis of mGluR5 has been studied in some detail, ligand-independent/constitutive endocytosis of the receptor has not been properly studied. Here, we have investigated the constitutive endocytosis of mGluR5 and also the sub-cellular fate of the receptor subsequent to internalization. We show here that mGluR5 undergoes constitutive internalization in HEK293 cells. Following endocytosis, the receptor enters the recycling compartment and no localization of the receptor was observed in the lysosome. In addition, we also report here that most of the receptors recycle to the cell surface subsequent to constitutive internalization. Thus, our data demonstrate that mGluR5 receptors internalize without the application of ligand and the internalized receptors recycle back to the cell surface following constitutive endocytosis.

Dendritic calcium signaling in cerebellar Purkinje cell

The Purkinje cells in the cerebellum are unique neurons that generate local and global Ca2+ signals in response to two types of excitatory inputs, parallel fiber and climbing fiber, respectively. The spatiotemporal distribution and interaction of these synaptic inputs produce complex patterns of Ca2+ dynamics in the Purkinje cell dendrites. The Ca2+ signals originate from Ca2+ influx through voltage-gated Ca2+ channels and Ca2+ release from intracellular stores that are mediated by the metabotropic glutamate receptor signaling pathway. These Ca2+ signals are essential for the induction of various forms of synaptic plasticity and for controlling the input–output relationship of Purkinje cells. In this article we review Ca2+ signaling in Purkinje cell dendrites.

Identification of mRNA for endocannabinoid biosynthetic enzymes within hippocampal pyramidal cells and CA1 stratum radiatum interneuron subtypes using quantitative real-time polymerase chain reaction

The hippocampus is required for short-term memory and contains both excitatory pyramidal cells and inhibitory interneurons. These cells exhibit various forms of synaptic plasticity, the mechanism underlying learning and memory. More recently, endocannabinoids were identified to be involved in synaptic plasticity. Our goal was to describe the distribution of endocannabinoid biosynthetic enzymes within CA1 stratum radiatum interneurons and CA3/CA1 pyramidal cells. We extracted mRNA from single interneurons and pyramidal cells and used real-time quantitative polymerase chain reaction (RT-PCR) to detect the presence of 12-lipoxygenase, N-acyl-phosphatidylethanolamine-specific phospholipase D, diacylglycerol lipase α, and type I metabotropic glutamate receptors, all known to be involved in endocannabinoid production and plasticity. We observed that the expression of endocannabinoid biosynthetic enzyme mRNA does occur within interneurons and that it is coexpressed with type I metabotropic glutamate receptors, suggesting interneurons have the potential to produce endocannabinoids. We also identified that CA3 and CA1 pyramidal cells express endocannabinoid biosynthetic enzyme mRNA. Our data provide the first molecular biological evidence for putative endocannabinoid production in interneurons, suggesting their potential ability to regulate endocannabinoid-mediated processes, such as synaptic plasticity.

Modulation of ATP-induced LTP by cannabinoid receptors in rat hippocampus.

Cannabinoids exert powerful action on various forms of synaptic plasticity. These retrograde messengers modulate GABA and glutamate release from presynaptic terminals by acting on presynaptic CB1 receptors. In particular, they inhibit long-term potentiation (LTP) elicited by electrical stimulation of excitatory pathways in rat hippocampus. Recently, LTP of the field excitatory postsynaptic potential (fEPSP) induced by exogenous ATP has been thoroughly explored. The present study demonstrates that cannabinoids inhibit ATP-induced LTP in hippocampal slices of rat. Administration of 10 μM of ATP led to strong inhibition of fEPSPs in CA1/CA3 hippocampal synapses. Within 40 min after ATP removal from bath solution, robust LTP was observed (fEPSP amplitude comprised 130.1 ± 3.8% of control, n = 10). This LTP never appeared when ATP was applied in addition to cannabinoid receptor agonist WIN55,212-2 (100 nM). Selective CB1 receptor antagonist, AM251 (500 nM), completely abolished this effect of WIN55,212-2. Our data indicate that like canonical LTP elicited by electrical stimulation, ATP-induced LTP is under control of CB1 receptors.

Pathology of Synapses and Dendritic Spines

Excitatory synapses represent the sites in which axons make a functional contact with their target neurons and they are typically located at the head of dendritic spines. Due to their critical role as mediators of interneuronal interactions, insults to synapses may result with significant clinical manifestations such as dementia or movement disorders. This special issue of Neural Plasticity discusses various aspects of synapse and spine pathology associated with Alzheimer's disease, perinatal asphyxia, and neuropathic pain. Synapse and spine loss may represent early and profound neuropathological changes potentially underlying cognitive deficits in Alzheimer's disease (AD). In fact, synapse loss is the strongest pathological correlate of dementia in AD. The inherent plasticity of synapses makes them an attractive therapeutic target. W. Yu and B. Lu, “Synapses and dendritic spines as pathogenic targets in Alzheimer's disease,” review the important field of synapse and dendritic loss in AD. In their paper, the authors discuss the well-established role of oligomeric amyloid beta in causing synaptic dysfunction and loss through signaling mechanisms associated with long-term depression. They also explore the exciting new relationship between amyloid beta and tau at the postsynaptic density. Several recent studies have placed tau in dendritic spines—a surprising place for a protein that dogma places firmly on microtubules in axons—where it is turning out to mediate amyloid-beta-induced synaptic dysfunction and loss. In another review T. Spires-Jones and S. Knafo, “Spines, plasticity, and cognition in Alzheimer's model mice,” provide a comprehensive analysis on recent works describing the morphological, synaptic, and behavioral characteristics of the different transgenic models of AD. Results from various models and in variety of ages show a gradual deterioration in synaptic and cognitive functions. The accumulating evidence from transgenic models discussed in this review appears to support a model of AD pathogenesis in which oligomeric amyloid beta initiates synaptic dysfunction or degeneration and induces pathological changes in tau, leading to neuronal loss and ultimately to cognitive deficits. G. E. Saraceno et al., “Hippocampal dendritic spines modifications induced by perinatal asphyxia,” investigated the effect of perinatal asphyxia (PA) on the hippocampal postsynaptic density (PSD). They report an unexpected increased thickness and dispersed appearance of the PSD in the asphyctic brains. Correlative fluorescent and electron microscopy showed a decline of F-actin-stained spines in hippocampal excitatory synapses after the insult that may suggest that PA is harmful to the actin cytoskeleton. These data suggest that perinatal asphyxia may lead to long-term changes in hippocampal synapses. NMDA receptors are located at synapses and modulate various forms of synaptic plasticity. Grin1b gene encodes the postsynaptic NMDA receptor in zebrafish. RNA and various RNA products play critical roles in regulating gene expression and production of neuroactive proteins in the nervous system. P. Pozo and B. Hoopengardner, “Identification and characterization of two novel RNA editing sites in grin1b transcripts of embryonic Danio rerio,” identified two novel RNA editing events for the grin1b gene in zebrafish. This new information may have implications for transcriptional regulation of mammalian glutamate receptors, which play essential roles in neuronal transmission and plasticity, but also mediate neuronal toxicity in neurodegenerative disorders. S. K. Kim et al., “Synaptic structure and function in the mouse somatosensory cortex during chronic pain: in vivo two-photon imaging,” summarize recent developments in studying in vivo spine dynamics in thesomatosensory cortex of adult mice in a model of chronic neuropathic pain. Thearticle highlights theimportance of neural plasticity in pain research. Employingmultiphoton microscopy, they describe remarkably rapid synaptic remodeling inlayer 5 neurons of somatosensory cortexwithin days of the peripheral nerveinjury (partial sciatic nerve ligation). Peripheral nerve injury via peripheralhyperactivity causes a rapid rewiring of distinct somatosensory cortexsynapticconnections, leading to local somatosensory cortex hyperexcitability. Theauthors postulate that these local cortical changes in spine turnover followinginduction of neuropathicpain play an important role in chronic pain conditions. Shira Knafo Gunnar K. Gouras Xiao-Xin Yan Tara Spires-Jones

Metaplasticity gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases

Metaplasticity is a higher form of synaptic plasticity that is essential for learning and memory, but its molecular mechanisms remain poorly understood. Here, we report that metaplasticity of transmission at CA1 synapses in the hippocampus is mediated by Src family kinase regulation of NMDA receptors (NMDARs). We found that stimulation of G-protein-coupled receptors (GPCRs) regulated the absolute contribution of GluN2A-versus GluN2B-containing NMDARs in CA1 neurons: pituitary adenylate cyclase activating peptide 1 receptors (PAC1Rs) selectively recruited Src kinase, phosphorylated GluN2ARs, and enhanced their functional contribution; dopamine 1 receptors (D1Rs) selectively stimulated Fyn kinase, phosphorylated GluN2BRs, and enhanced these currents. Surprisingly, PAC1R lowered the threshold for long-term potentiation while long-term depression was enhanced by D1R. We conclude that metaplasticity is gated by the activity of GPCRs, which selectively target subtypes of NMDARs via Src kinases.

Involvement of Synaptic NR2B-Containing NMDA Receptors in Long-Term Depression Induction in the Young Rat Visual Cortex In Vitro

Activation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in the induction of long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) in layer II/III pyramidal neurons of the young rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A- and NR2B-containing NMDARs in the induction of LTD in visual cortical slices from 12- to 15-day old rats. We found that LTD was readily induced in layer II/III pyramidal neurons of the rat visual cortex with 10-min 1-Hz stimulation paired with postsynaptic depolarization. D-APV, a selective NMDAR antagonist, blocked the induction of LTD. Moreover, the selective NR2B-containing NMDAR antagonists (Ro 25-6981 and ifenprodil) also prevented the induction of LTD. However, Zn2+, a voltage-independent NR2A-containing NMDAR antagonist, displayed no influence on the induction of LTD. These results suggest that the induction of LTD in layer II/III pyramidal neurons of the young rat visual cortex is NMDAR-dependent and requires NR2B-containing NMDARs, not NR2A-containing NMDARs.

Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink?

Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink?

Acute knockdown of AMPA receptors reveals a trans-synaptic signal for presynaptic maturation

Newly formed glutamatergic synapses often lack postsynaptic AMPA-type glutamate receptors (AMPARs). Aside from 'unsilencing' the postsynaptic site, however, the significance of postsynaptic AMPAR insertion during synapse maturation remains unclear. To investigate the role of AMPAR in synapse maturation, we used RNA interference (RNAi) to knockdown AMPARs in cultured hippocampal neurons. Surprisingly, loss of postsynaptic AMPARs increased the occurrence of presynaptically inactive synapses without changing the release probability of the remaining active synapses. Additionally, heterologous synapses formed between axons and AMPAR-expressing HEK cells develop significantly fewer inactive presynaptic terminals. The extracellular domain of the AMPAR subunit GluA2 was sufficient to reproduce this effect at heterologous synapses. Indeed, the retrograde signalling by AMPARs is independent of their channel function as RNAi-resistant AMPARs restore synaptic transmission in neurons lacking AMPARs despite chronic receptor antagonist treatment. Our findings suggest that postsynaptic AMPARs perform an organizational function at synapses that exceeds their standard role as ionotropic receptors by conveying a retrograde trans-synaptic signal that increases the transmission efficacy at a synapse.

A novel non‐CB1/TRPV1 endocannabinoid‐mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons

Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long-term depression at excitatory synapses on CA1 hippocampal stratum radiatum interneurons. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well as the involvement of Group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the nonhydrolysable anandamide analog R-methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by ∼50%. The Group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10 μM) but not by the mGluR1 antagonist CPCCOEt (50 μM). Interestingly, however, neither DHPG-mediated nor R-methanandamide-mediated depression was blocked by the TRPV1 antagonist capsazepine (10 μM), the CB1 antagonist AM-251 (2 μM) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R-methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1-independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons.

Perisynaptic Glia Discriminate Patterns of Motor Nerve Activity and Influence Plasticity at the Neuromuscular Junction

In the nervous system, the induction of plasticity is coded by patterns of synaptic activity. Glial cells are now recognized as dynamic partners in a wide variety of brain functions, including the induction and modulation of various forms of synaptic plasticity. However, it appears that glial cells are usually activated by stereotyped, sustained neuronal activity, and little attention has been given to more subtle changes in the patterns of synaptic activation. To this end, we used the mouse neuromuscular junction as a simple and useful model to study glial modulation of synaptic plasticity. We used two patterns of motor nerve stimulation that mimic endogenous motor-neuronal activity. A continuous stimulation induced a post-tetanic potentiation and a phasic Ca(2+) response in perisynaptic Schwann cells (PSCs), glial cells at this synapse. A bursting pattern of activity induced a post-tetanic depression and oscillatory Ca(2+) responses in PSCs. The different Ca(2+) responses in PSCs indicate that they decode the pattern of synaptic activity. Furthermore, the chelation of glial Ca(2+) impaired the production of the sustained plasticity events indicating that PSCs govern the outcome of synaptic plasticity. The mechanisms involved were studied using direct photo-activation of PSCs with caged Ca(2+) that mimicked endogenous plasticity. Using specific pharmacology and transgenic knock-out animals for adenosine receptors, we showed that the sustained depression was mediated by A1 receptors while the sustained potentiation is mediated by A(2A) receptors. These results demonstrate that glial cells decode the pattern of synaptic activity and subsequently provide bidirectional feedback to synapses.

Differential Regulation of Kainate Receptor Trafficking by Phosphorylation of Distinct Sites on GluR6

Kainate receptors are widely expressed in the brain, and are present at pre- and postsynaptic sites where they play a prominent role in synaptic plasticity and the regulation of network activity. Within individual neurons, kainate receptors of different subunit compositions are targeted to various locations where they serve distinct functional roles. Despite this complex targeting, relatively little is known about the molecular mechanisms regulating kainate receptor subunit trafficking. Here we investigate the role of phosphorylation in the trafficking of the GluR6 kainate receptor subunit. We identify two specific residues on the GluR6 C terminus, Ser(846) and Ser(868), which are phosphorylated by protein kinase C (PKC) and dramatically regulate GluR6 surface expression. By using GluR6 containing phosphomimetic and nonphosphorylatable mutations for these sites expressed in heterologous cells or in neurons lacking endogenous GluR6, we show that phosphorylation of Ser(846) or Ser(868) regulates receptor trafficking through the biosynthetic pathway. Additionally, Ser(846) phosphorylation dynamically regulates endocytosis of GluR6 at the plasma membrane. Our findings thus demonstrate that phosphorylation of PKC sites on GluR6 regulates surface expression of GluR6 at distinct intracellular trafficking pathways, providing potential molecular mechanisms for the PKC-dependent regulation of synaptic kainate receptor function observed during various forms of synaptic plasticity.

Regulation of the Proteasome by Neuronal Activity and Calcium/Calmodulin-dependent Protein Kinase II

Protein degradation via the ubiquitin proteasome system has been shown to regulate changes in synaptic strength that underlie multiple forms of synaptic plasticity. It is plausible, therefore, that the ubiquitin proteasome system is itself regulated by synaptic activity. By utilizing live-cell imaging strategies we report the rapid and dynamic regulation of the proteasome in hippocampal neurons by synaptic activity. We find that the blockade of action potentials (APs) with tetrodotoxin inhibited the activity of the proteasome, whereas the up-regulation of APs with bicuculline dramatically increased the activity of the proteasome. In addition, the regulation of the proteasome is dependent upon external calcium entry in part through N-methyl-D-aspartate receptors and L-type voltage-gated calcium channels and requires the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). Using in vitro and in vivo assays we find that CaMKII stimulates proteasome activity and directly phosphorylates Rpt6, a subunit of the 19 S (PA700) subcomplex of the 26 S proteasome. Our data provide a novel mechanism whereby CaMKII may regulate the proteasome in neurons to facilitate remodeling of synaptic connections through protein degradation.

NR2A-containing NMDA receptors are required for LTP induction in rat dorsolateral striatum in vitro

N-methyl- d-aspartate receptors (NMDARs) have been implicated in various forms of synaptic plasticity. In recent years, studies have been shown that NMDA receptor subunits play different roles in several forms of NMDAR-dependent synaptic plasticity. However, the contribution of NR2A and NR2B subunits in the induction of long-term potentiation (LTP) in the corticostriatal pathway remains unclear. The present study used patch-clamp recordings to study the role of NR2A-containing and NR2B-containing NMDARs in LTP induction in corticostriatal slices from 13–14-day old rats. High-frequency stimulation (HFS) of the corticostriatal pathway readily induced LTP of excitatory postsynaptic currents (EPSCs), and D-APV, a selective NMDAR antagonist, blocked LTP. Moreover, NR2B-containing NMDAR antagonists (Ro 25-6981 and ifenprodil) displayed no influence on LTP induction. However, LTP was not inducible in the presence of Zn 2+, an NR2A-containing NMDAR antagonist. These results suggest that the induction of LTP by HFS in the dorsolateral striatum is NMDAR-dependent and requires NR2A-containing NMDARs, not NR2B-containing NMDARs.

Targeting inhibition of GluR1 Ser845 phosphorylation with an RNA aptamer that blocks AMPA receptor trafficking

Phosphorylation at glutamate receptor subunit 1(GluR1) Ser845 residue has been widely accepted to involve in GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking, but the in vivo evidence has not yet been established. One of the main obstacles is the lack of effective methodologies to selectively target phosphorylation at single amino acid residue. In this study, the Escherichia coli-expressed glutathione-S-transferase-tagged intracellular carboxyl-terminal domain of GluR1 (cGluR1) was phosphorylated by protein kinase A for in vitro selection. We have successfully selected aptamers which effectively bind to phospho-Ser845 cGluR1 protein, but without binding to phospho-Ser831 cGluR1 protein. Moreover, pre-binding of the unphospho-cGluR1 protein with these aptamers inhibits protein kinase A-mediated phosphorylation at Ser845 residue. In contrast, the pre-binding of aptamer A2 has no effect on protein kinase C-mediated phosphorylation at Ser831 residue. Importantly, the representative aptamer A2 can effectively bind the mammalian GluR1 that inhibited GluR1/GluR1-containing AMPA receptor trafficking to the cell surface and abrogated forskolin-stimulated phosphorylation at GluR1 Ser845 in both green fluorescent protein-GluR1-transfected human embryonic kidney cells and cultured rat cortical neurons. The strategy to use aptamer to modify single-residue phosphorylation is expected to facilitate evaluation of the potential role of AMPA receptors in various forms of synaptic plasticity including that underlying psychostimulant abuse.

Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation

BackgroundEstablished traumatic memories have a selective vulnerability to pharmacologic interventions following their reactivation that can decrease subsequent memory recall. This vulnerable period following memory reactivation is termed reconsolidation. The pharmacology of traumatic memory reconsolidation has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders including posttraumatic stress disorder (PTSD). The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is known to be involved in various forms of synaptic plasticity and memory consolidation. We have examined the role of mTOR in traumatic memory reconsolidation. MethodsMale C57BL/6 mice were injected systemically with the mTOR inhibitor rapamycin (1–40mg/kg), at various time points relative to contextual fear conditioning training or fear memory retrieval, and compared to vehicle or anisomycin-treated groups (N=10–12 in each group). ResultsInhibition of mTOR via systemic administration of rapamycin blocks reconsolidation of an established fear memory in a lasting manner. This effect is specific to reconsolidation as a series of additional experiments make an effect on memory extinction unlikely. ConclusionsSystemic rapamycin, in conjunction with therapeutic traumatic memory reactivation, can decrease the emotional strength of an established traumatic memory. This finding not only establishes mTOR regulation of protein translation in the reconsolidation phase of traumatic memory, but also implicates a novel, FDA-approved drug treatment for patients suffering from acquired anxiety disorders such as PTSD and specific phobia.

Compartmentalized dendritic plasticity and input feature storage in neurons

Although information storage in the central nervous system is thought to be primarily mediated by various forms of synaptic plasticity, other mechanisms, such as modifications in membrane excitability, are available. Local dendritic spikes are nonlinear voltage events that are initiated within dendritic branches by spatially clustered and temporally synchronous synaptic input. That local spikes selectively respond only to appropriately correlated input allows them to function as input feature detectors and potentially as powerful information storage mechanisms. However, it is currently unknown whether any effective form of local dendritic spike plasticity exists. Here we show that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an N-methyl-d-aspartate receptor (NMDAR)-dependent regulation of dendritic Kv4.2 potassium channels. These data suggest that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatio-temporal correlation. We propose that this 'branch strength potentiation' represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.

Signaling via CNS cannabinoid receptors

Because of the prominent psychoactive effects of cannabis and its preparations, much research has focused on the actions of cannabinoids, the primary psychoactive components of cannabis, on neuronal function. A convergence of research has identified (1) cannabinoid receptors, (2) endogenous compounds that activate these receptors (endocannabinoids), and (3) drugs that interact with these receptors and the proteins that synthesize and degrade the endocannabinoids. This review will first consider how endogenous cannabinoids signal through cannabinoid receptors and the various forms of synaptic plasticity mediated by endocannabinoids. Next the interactions between exogenous cannabinoids such as Delta9-tetrahydrocannabinol and endocannabinoids and endocannabinoid-mediated plasticity will be examined. Finally, a model will be presented that can explain the prominent psychoactivity of these plant-derived cannabinoids.