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Highlights: [•] Neuronal nitric oxide synthase is necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia. [•] Episodic spinal NO is sufficient to elicit facilitation of phrenic nerve activity (pMF). [•] NO-induced pMF involves 5-HT2B receptors and spinal NADPH oxidase activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] Actin cytoskeleton and its regulatory proteins are needed for memory formation. [•] Actin cytoskeleton and its regulatory proteins are essential for synaptic plasticity. [•] Actin cytoskeleton is involved in synaptic transmission and neuronal morphogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction. [Copyright &y& Elsevier]

Highlights: [•] Excitotoxicity is a primary mechanism of neuronal injury following stroke. [•] Excitotoxicity requires influx of calcium ion through the NMDA receptor. [•] Different subpopulations of the NMDA receptor elicit distinct functional output. [•] NMDA receptor promotes neuronal death or survival depending on what's downstream. [•] Studying downstream signaling events allows development of better stroke treatments. [ABSTRACT FROM AUTHOR]

Abstract: Rare disorders leading to intellectual disability, such as Fragile X syndrome (FXS) alter synaptic plasticity. Ligand identification of orphan nuclear receptors has led to the discovery of many signaling pathways and has revealed a direct link of nuclear receptors with human conditions such as mental retardation and neurodegenerative diseases. PPARγ agonists can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth. Therefore, selective PPARγ agonists are good candidates for therapeutic evaluation in intellectual disabilities. Preliminary results suggest that PPARγ agonists such as Pioglitazone, Rosiglitazone and synthetic agonist, GW1929, are used as the therapeutic agent in neurological disorders. These components interact with intracellular transduction signals (e.g. GSK3β, PI3K/Akt, Wnt/β-Catenin, Rac1 and MMP-9). It seems that interaction with these pathways can improve memory recognition in FXS animal models. The present hypothesis consists of enhancing synaptic plasticity that may then rescue the learning and memory in FXS. This will open many new therapeutic avenues for a variety of human diseases. [Copyright &y& Elsevier]

Highlights: [•] Long-term potentiation was measured in hippocampal slices from two mouse strains. [•] The level of long-term potentiation is different in one strain than the other. [•] Social isolation stress reduces long-term potentiation expression in both strains. [•] Corticosterone levels increase after social stress isolation. [•] Long-term potentiation was restored by glucocorticoid receptor antagonist. [ABSTRACT FROM AUTHOR]

Highlights: [•] An inhibitor of kynurenine-3-monoxygenase was administered to pregnant female rats. [•] Adult offspring at postnatal day 60 (P60) showed alterations in synaptic plasticity. [•] Expression of GluN2A, sonic hedgehog and other developmental proteins was changed. [•] Most earlier protein changes had disappeared with no changes in RNA or learning tasks. [•] Prenatal kynurenine pathway inhibition produces persistent synaptic and protein changes. [Copyright &y& Elsevier]

Abstract: The cyclic nucleotides cAMP and cGMP are common signalling molecules synthesized in neurons following the activation of adenylyl or guanylyl cyclase. In the striatum, the synthesis and degradation of cAMP and cGMP is highly regulated as these second messengers have potent effects on the activity of striatonigral and striatopallidal neurons. This review will summarize the literature on cyclic nucleotide signalling in the striatum with a particular focus on the impact of cAMP and cGMP on the membrane excitability of striatal medium-sized spiny output neurons (MSNs). The effects of non-selective and selective phosphodiesterase (PDE) inhibitors on membrane activity and synaptic plasticity of MSNs will also be reviewed. Lastly, this review will discuss the implications of the effects PDE modulation on electrophysiological activity of striatal MSNs as it relates to the treatment of neurological disorders such as Huntington's and Parkinson's disease. [Copyright &y& Elsevier]

Abstract: Abnormalities in dendritic spines have commonly been observed in brain specimens from epilepsy patients and animal models of epilepsy. However, the functional implications and clinical consequences of this dendritic pathology for epilepsy are uncertain. Dendritic spine abnormalities may promote hyperexcitable circuits and seizures in some types of epilepsy, especially in specific genetic syndromes with documented dendritic pathology, but in these cases it is difficult to differentiate their effects on seizures versus other comorbidities, such as cognitive deficits and autism. In other situations, seizures themselves may cause damage to dendrites and dendritic spines and this seizure-induced brain injury may then contribute to progressive epileptogenesis, memory problems and other neurological deficits in epilepsy patients. The mechanistic basis of dendritic spine abnormalities in epilepsy has begun to be elucidated and suggests novel therapeutic strategies for treating epilepsy and its complications. [Copyright &y& Elsevier]

Highlights: [•] Adolescence is a period of significant neurobiological and behavioral change. [•] Adolescence is a time when individuals first use drugs and alcohol. [•] Adolescents may be especially sensitive to drug-induced plasticity. [•] We review evidence suggesting adolescence is a period of high vulnerability. [ABSTRACT FROM AUTHOR]

Highlights: [•] Stress can result in highly adaptive responses but is also an important risk factor for disease. [•] Acute stress rapidly enhances excitatory synaptic transmission and promotes learning and memory processes. [•] Chronic stress reduces excitatory synaptic transmission and learning and memory. [•] Early life experience has long-lasting effects on excitatory synaptic transmission and dendritic complexity. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examine the effect of tDCS alone or grip exercise alone or combination of tDCS and grip exercise. [•] Simultaneous administration of real tDCS and grip exercise led to the most significant increase in MEP amplitude. [•] Real tDCS alone and grip exercise alone resulted in similar increases in MEP amplitude. [ABSTRACT FROM AUTHOR]

Abstract: Pharmacological and behavior interventions for inhibiting fear and anxiety are important in the treatment of different types of anxiety disorder. Fear extinction, as a novel form of associative learning, is the most extensively studied models to understand the neural mechanisms of fear-related and anxiety disorders. One of the possible mechanisms of neural plasticity in extinction learning may depend on activation of NMDA receptors in the amygdale; however, the role played by the hippocampus in extinction remains largely unclear. In the present study, using a fear conditioning paradigm, we repeatedly microinfused d-cycloserine, a partial agonist of NMDA receptor, into the hippocampus and investigated the effects of repeated infusions of DCS on extinction behavior and protein levels of NMDA receptor subunit NR2B. We also examined the effects of DCS on neurogenesis in adult rat hippocampus. Our results showed that the administration of DCS facilitated the acquisition and retrieval of extinction memory, and enhanced the expression of NR2B protein in the dentate gyrus, CA1 and CA3 of the hippocampus. We also found that repeated microinfusions of DCS increased proliferation of newly born cells in the hippocampus. These findings suggest that neural plasticity mediated by NMDA receptors in the hippocampus is involved in the enhancement of acquisition and retrieval of extinction memory. [Copyright &y& Elsevier]

Abstract: Purpose: Thus far, no promising drug for Alzheimer disease has been developed. Previously, we documented the beneficial effects of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DL-PC) and/or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (PO-PC), which enhanced learning and memory abilities and improved cognitive disorders in both animals and humans. The present study reviews the usefulness of DL- and PO-PC for the treatment of Alzheimer dementia. Study section and results: The anti-dementia effect of DL-PC, PO-PC, or DL-PC plus PO-PC was assessed in patients with cognitive decline and dementia by using the Mini-Mental State Examination (MMSE) test. The initial MMSE score for the patients was 17.4 ± 0.3; however, 1 month after taking DL- and/or PO-PC the score increased to over 20, corresponding to normal cognitive functions, and the effect was still evident in some subjects 5 years after taking DL- and/or PO-PC. Among the subjects in this study, 20 patients with Alzheimer disease had taken donepezil hydrochloride for more than 1 year. The MMSE score for those 20 patients was 11.8 ± 1.1, and the score significantly improved to 19.9 ± 1.6 one year after stopping donepezil medication and instead taking DL- and PO-PC. Conclusion: The results of the present study demonstrate that DL-/PO-PC could be an effective therapeutic agent for Alzheimer dementia. [Copyright &y& Elsevier]

Background: Maternal infection during pregnancy is a recognized risk factor for the occurrence of a broad spectrum of psychiatric and neurologic disorders, including schizophrenia, autism, and cerebral palsy. Prenatal exposure of rats to lipopolysaccharide (LPS) leads to impaired learning and psychotic-like behavior in mature offspring, together with an enduring modification of glutamatergic excitatory synaptic transmission. The question that arises is whether any alterations of excitatory transmission and plasticity occurred at early developmental stages after in utero LPS exposure. Methods: Electrophysiological experiments were carried out on the CA1 area of hippocampal slices from prenatally LPS-exposed male offspring from 4 to 190 days old to study the developmental profiles of long-term depression (LTD) triggered by delivering 900 shocks either single- or paired-pulse (50-msec interval) at 1 Hz and the N-methyl-D-aspartate receptor (NMDAr) contribution to synaptic transmission. Results: The age-dependent drop of LTD is accelerated in prenatally LPS-exposed animals, and LTD is transiently converted into a slow-onset long-term potentiation between 16 and 25 days old. This long-term potentiation depends on Group I metabotropic glutamate receptors and protein kinase A activations and is independent of NMDArs. Maternal LPS challenge also leads to a rapid developmental impairment of synaptic NMDArs. This was associated with a concomitant reduced expression of GluN1, without any detectable alteration in the developmental switch of NMDAr GluN2 subunits. Conclusions: Aberrant forms of synaptic plasticity can be detected at early developmental stages after prenatal LPS challenge concomitant with a clear hypo-functioning of the NMDAr in the hippocampus. This might result in later-occurring brain dysfunctions. [Copyright &y& Elsevier]

Abstract: In this study, we have investigated the effects of 17β-estradiol (E2) on chemically induced long-term depression (LTD). LTD was induced by a brief application of N-methyl-d-aspartate (NMDA) or (R,S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor agonist. Bath application of E2 alone potentiated population excitatory postsynaptic potentials. This potentiation was readily reversed by washing with control saline. The effect of E2 on NMDA-induced LTD was a conversion of LTD to long-term potentiation (LTP). An application of NMDA in the presence of E2 induced LTP. The induction of LTP was inhibited by an inhibitor of calcium/calmodulin dependent protein kinase (CaMKII). The results suggest that E2 potentiates NMDA receptor function and induces an increase in postsynaptic Ca2+ concentration. An increase in postsynaptic Ca2+ concentration activates CaMKII, leading to LTP. In contrast to NMDA-induced LTD, an application of DHPG in the presence of E2 induced significantly larger LTD. The results suggest that E2 potentiates an as yet unidentified process(es) in inducing LTD by an application of DHPG. The effects of E2 both on NMDA-induced and DHPG-induced LTD were suppressed by an estrogen receptor antagonist. [Copyright &y& Elsevier]

Abstract: This paper is the 26th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2003 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular–biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). [Copyright &y& Elsevier]

Orexins (OX), also called hypocretins, are bioactive peptides secreted from glucose-sensitive neurons in the lateral hypothalamus linking appetite, arousal and neuroendocrine-autonomic control. Here, OX-A was found to cause a slow-onset long-term potentiation of synaptic transmission (LTPOX) in the hippocampus of young adult mice. LTPOX was induced at Schaffer collateral-CA1 but not mossy fiber-CA3 synapses, and required transient sharp wave-concurrent population field-burst activity generated by the autoassociative CA3 network. Exogenous long θ-frequency stimulation of Schaffer collateral axons erased LTPOX in intact hippocampal slices but not mini slices devoid of the CA3 region. Pharmacological analysis revealed that LTPOX requires co-activation of ionotropic and metabotropic glutamatergic, GABAergic, as well as noradrenergic and cholinergic receptors. Together these data indicate that OX-A induces a state-dependent metaplasticity in the CA1 region associated with sharp-wave and θ rhythm activity as well as glutamatergic, GABAergic, aminergic, and cholinergic transmission. Thus, orexins not only regulate arousal threshold and body weight but also threshold and weight of synaptic connectivity, providing a molecular prerequisite for homeostatic and behavioral state-dependent control of neuronal plasticity and presumably memory functions. [Copyright &y& Elsevier]

A major question in the study of cerebellar cortical function is how parallel fiber and climbing fiber inputs interact to shape information processing. Emphasis has been placed on the long-term effects due to conjunctive stimulation of climbing fibers and parallel fibers. Much less emphasis has been placed on short-term interactions and their spatial nature. To address this question the responses to parallel fiber and climbing fiber inputs and their short-term interaction were characterized using optical imaging with Neutral Red in the anesthetized mouse in vivo. Electrical stimulation of the cerebellar surface evoked an increase in fluorescence consisting of a transverse optical beam. The linear relationship between the optical responses and stimulus parameters, high spatial resolution and close coupling to the electrophysiological recordings show the utility of this imaging methodology. The majority of the optical response was due to activation of postsynaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors with a minor contribution from the presynaptic parallel fibers. Stimulation of the inferior olive evoked parasagittal bands that were abolished by blocking AMPA glutamate receptors. Conjunctive stimulation of the cerebellar surface and inferior olive resulted in inhibition of the climbing fiber evoked optical responses. This lateral inhibition of the parasagittal bands extended out from both sides of an activated parallel fiber beam and was mediated by GABAA but not GABAB receptors. One hypothesized role for lateral inhibition of this type is to spatially focus the interactions between parallel fiber and climbing fiber input on Purkinje cells.In summary optical imaging with Neutral Red permitted visualization of cerebellar cortical responses to parallel fiber and climbing fiber activation. The GABAA dependent lateral inhibition of the climbing fiber evoked parasagittal bands by parallel fiber stimulation shows that cerebellar interneurons play a short-term role in shaping the responses of Purkinje cells to climbing fiber input. [Copyright &y& Elsevier]

Recent data indicate that most “silent” synapses in the hippocampus are “presynaptically silent” due to low transmitter release rather than “postsynaptically silent” due to “latent” receptors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type (AMPARs). That synapses bearing only N-methyl-d-aspartate (NMDAR) receptors do exist is suggested by the decreased number of transmission failures during postsynaptic depolarisation and by the presence of NMDA-mediated excitatory postsynaptic currents (EPSCs) in synapses silent at rest. We tested whether these effects could be due to potentiated transmitter release at depolarised postsynaptic potentials rather than removal of Mg2+ block from NMDARs. Using whole-cell recordings of minimal EPSCs from CA1 and CA3 neurones of hippocampal slices we confirmed decreased incidence of failures at +40 mV as compared with -60 mV. This effect was associated with a gradual increase of EPSC amplitude after switching to +40 mV and with a decrease of paired-pulse facilitation. In initially silent synapses, potentiation of pharmacologically isolated AMPAR-mediated EPSCs was still observed at +40 mV and this persisted after stepping back to -60 mV. All above effects were blocked when the cell was dialysed with the Ca2+ chelator BAPTA (20 mM). These observations are difficult to reconcile with the “latent AMPAR” hypothesis and suggest an alternative explanation, namely that the reduction in failure rates at positive potentials is due to potentiation of transmitter release following Ca2+ influx through NMDARs. Our results suggest that silent synapses can be mainly “presynaptically” rather than “postsynaptically silent” and thus increased transmitter release rather than insertion of AMPARs is a major mechanism of early long-term potentiation maintenance. [Copyright &y& Elsevier]

Retinoic acid modulates a wide variety of biological processes including proliferation, differentiation, and apoptosis. It interacts with specific receptors in the nucleus, the retinoic acid receptors (RARs). The molecular mechanism by which retinoic acid mediates cellular differentiation and growth suppression in neural cells remains unknown. However, retinoic acid-induced release of arachidonic acid and its metabolites may play an important role in cell proliferation, differentiation, and apoptosis. In brain tissue, arachidonic acid is mainly released by the action of phospholipase A2 (PLA2) and phospholipase C (PLC)/diacylglycerol lipase pathways. We have used the model of differentiation in LA-N-1 cells induced by retinoic acid. The treatment of LA-N-1 cells with retinoic acid produces an increase in phospholipase A2 activity in the nuclear fraction. The pan retinoic acid receptor antagonist, BMS493, can prevent this increase in phospholipase A2 activity. This suggests that retinoic acid-induced stimulation of phospholipase A2 activity is a retinoic acid receptor-mediated process. LA-N-1 cell nuclei also have phospholipase C and phospholipase D (PLD) activities that are stimulated by retinoic acid. Selective phospholipase C and phospholipase D inhibitors block the stimulation of phospholipase C and phospholipase D activities. Thus, both direct and indirect mechanisms of arachidonic acid release exist in LA-N-1 cell nuclei. Arachidonic acid and its metabolites markedly affect the neurite outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that retinoic acid receptors coupled with phospholipases A2, C and D in the nuclear membrane play an important role in the redistribution of arachidonic acid in neuronal and non-nuclear neuronal membranes during differentiation and growth suppression. Abnormal retinoid metabolism may be involved in the downstream transcriptional regulation of phospholipase A2-mediated signal transduction in schizophrenia and Alzheimer disease (AD). The development of new retinoid analogs with diminished toxicity that can cross the blood–brain barrier without harm and can normalize phospholipase A2-mediated signaling will be important in developing pharmacological interventions for these neurological disorders. [Copyright &y& Elsevier]

The negative impact of chronic stress at the structure of apical dendrite branches of cornu ammonis 3 (CA3) pyramidal neurons is well established. However, there is no information available on the CA3 dendritic organization related to short-lasting stress, which suffices to produce long-term habituation or sensitization of anxiety behaviors and neuroendocrine responses. Here, we tested the effects evoked by brief stress on the arrangements of CA3 pyramidal neuron dendrites, and the activity-dependent properties of the commissural-associational (C/A) excitatory postsynaptic potentials (EPSPs). Adult male rats were socially defeated followed by 3 weeks without further treatment or as comparison exposed to a regimen of a social defeat every second day for the same time period. We assessed CA3 pyramidal neurons with somatic whole-cell recording and neurobiotin application in acute hippocampal slices. The results from morphometric analysis of post hoc reconstructions demonstrated that CA3 dendrites from repeatedly stressed rats were reduced in surface area and length selectively at the apical cone (70% of control, approximately 280 μm from the soma). Brief stress, however, produced a similar decrease in apical dendritic length (77% of control, approximately 400 μm from the soma), accompanied by an increased length (167% of control) and branch complexity at the basal cone. The structural changes of the dendrites significantly influenced signal propagation by shortening the onset latency of EPSPs and increasing input resistance (r=0.45, P<0.01), of which the first was significantly changed in repeatedly stressed animals. Both brief and repeated stress long-lastingly impaired long-term potentiation of C/A synapses to a similar degree (P<0.05). These data indicate that the geometric plasticity of CA3 dendrites is dissociated from repetition of aversive experiences. A double social conflict suffices to drive a dynamic reorganization, by site-selective elimination and de novo growth of dendrite branches over the course of weeks after the actual experience. [Copyright &y& Elsevier]

N-Methyl-d-aspartate (NMDA) glutamate receptors are a class of excitatory amino acid receptors, which have several important functions in the motor circuits of the basal ganglia, and are viewed as important targets for the development of new drugs to prevent or treat Parkinson''s disease (PD). NMDA receptors are ligand-gated ion channels composed of multiple subunits, each of which has distinct cellular and regional patterns of expression. They have complex regulatory properties, with both agonist and co-agonist binding sites and regulation by phosphorylation and protein-protein interactions. They are found in all of the structures of the basal ganglia, although the subunit composition in the various structures is different. NMDA receptors present in the striatum are crucial for dopamine-glutamate interactions. The abundance, structure, and function of striatal receptors are altered by the dopamine depletion and further modified by the pharmacological treatments used in PD. In animal models, NMDA receptor antagonists are effective antiparkinsonian agents and can reduce the complications of chronic dopaminergic therapy (wearing off and dyskinesias). Use of these agents in humans has been limited because of the adverse effects associated with nonselective blockade of NMDA receptor function, but the development of more potent and selective pharmaceuticals holds the promise of an important new therapeutic approach for PD. [Copyright &y& Elsevier]

The pro-inflammatory cytokine tumor-necrosis factor-α (TNF-α) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF-α inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF-α prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68±5%, n=6 versus control 175±7%, n=6, P<0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF-α as p38 MAPK has previously been shown to be involved in interleukin-1β inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF-α led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 μM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF-α (SB/TNF-α 174±5%, n=6 versus TNF-α 120±7%, n=6, P<0.001, 1 h post-tetanus) to values comparable to control LTP (control 175±7%, n=6). Interestingly however, the depressive effects of TNF-α on late LTP (2–3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF-α 132±5%, n=6 versus control LTP 175±7%, n=6, P<0.001, 3 h post-tetanus). This work suggests that TNF-α inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP. [Copyright &y& Elsevier]

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83±10%, n=5, P<0.01, compared with controls of 160±11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63±1% at 100 ng/ml, n=5 and 66±1% at 200 ng/ml, n=4, compared to controls of 56±6%, n=6). Manumycin A (2μM) had no effect on LTP (162±2%, n=5, compared to controls of 167±13%, n=5), but significantly attenuated LTD (88±6%, n=5, P<0.01, compared to controls of 63±9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240±40%, n=5, P<0.01, compared with controls of 100±4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92±2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP. [Copyright &y& Elsevier]

The brain renin–angiotensin system (RAS) has long been known to regulate several classic physiologies including blood pressure, sodium and water balance, cyclicity of reproductive hormones and sexual behaviors, and pituitary gland hormones. These physiologies are thought to be under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AT2 receptor subtype is expressed during fetal development and is less abundant in the adult. This receptor appears to oppose growth responses facilitated by the AT1 receptor, as well as growth factor receptors. Recent evidence points to an important contribution by the brain RAS to non-classic physiologies mediated by the newly discovered angiotensin IV (AngIV)/AT4 receptor subtype system. These physiologies include the regulation of blood flow, modulation of exploratory behavior, and a facilitory role in learning and memory acquisition. This system appears to interact with brain matrix metalloproteinases in order to modify extracellular matrix molecules thus permitting the synaptic remodeling critical to the neural plasticity presumed to underlie memory consolidation, reconsolidation, and retrieval. There is support for an inhibitory influence by AngII activation of the AT1 subtype, and a facilitory role by AngIV activation of the AT4 subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning. The discovery of the AT4 receptor subtype, and its facilitory influence upon learning and memory, suggest an important role for the brain RAS in normal cognitive processing and perhaps in the treatment of dysfunctional memory disease states. [Copyright &y& Elsevier]

Prior studies showed that positive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-d-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus.Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding. [Copyright &y& Elsevier]

Sensory experience drives plasticity of the body map in developing and adult somatosensory cortex, but the synaptic mechanisms underlying such plasticity are not well understood. Recently, several mechanisms that are likely to contribute to map plasticity have been directly observed in response to altered experience in vivo. These mechanisms include long-term potentiation and long-term depression at specific excitatory synapses, competition between lemniscal (barrel) and non-lemniscal (septal) processing streams, and regulation of the number of inhibitory synapses. [Copyright &y& Elsevier]

Correlated pre- and postsynaptic activity is thought to promote maturation of excitatory synapses in the developing brain by directing AMPA receptors to pure NMDA synapses. However, this hypothesis has not been tested in vivo. Here, we have performed such test by inhibiting correlated neural activity in vivo using a single injection of tetanus toxin into the rat hippocampal CA1 area at postnatal day 1. When examined in the acute slice preparation (1–7 days post-injection), there was a strong reduction, down to 20% of control level, in the frequency of glutamatergic and GABAergic spontaneous postsynaptic currents (sPSCs). This activity deprivation led to a growth retardation of CA1 pyramidal neurons and to markedly faster decay kinetics of NMDA sPCSs. However, it did not alter the relationship between AMPA and NMDA sPSCs with respect to either their frequency or amplitude. Thus, although critical for certain aspects of neuronal development, correlated neural activity in the neonatal hippocampus does not seem to promote incorporation of AMPA receptors at pure NMDA synapses. [Copyright &y& Elsevier]

Brain plasticity refers to the ability of the brain to undergo structural and functional changes. It is a necessary process that allows us to adapt and learn from our environment and is fundamental to our survival. However, under certain conditions, these neuroadaptive responses can have adverse consequences. In particular, increasing evidence indicates that plastic processes are coopted by drugs of abuse, leading to addiction and associated drug-seeking behaviors. An extensive and diverse group of studies ranging from the molecular to the behavioral level has also strongly implicated glutamatergic neurotransmission as a critical mediator of experience-dependent synaptic plasticity. Thus, it is vital to understand how drugs of abuse interact and potentially alter glutamatergic neurotransmission and associated signal transduction processes. This review will focus on the cellular and molecular neuroscience of alcoholism, with emphasis on events at the glutamatergic postsynaptic density (PSD) and dendritic spine dynamics that appear to underlie much of the structural and functional plasticity of the CNS. [Copyright &y& Elsevier]

Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (hypocretin-1) and orexin-B (hypocretin-2) and send their axons to the hippocampus, which predominantly expresses orexin receptor 1 showing a higher sensitivity to orexin-A. The purpose of the present study was to assess the effects of orexin-A on the performance of Wistar rats during the Morris water maze test and then to determine the effects of orexin-A on both the long-term potentiation and long-term depression in Schaffer collateral/commissural-CA1 synapses in hippocampal slices. The results of the Morris water maze test show that 1.0 and 10 nmol of orexin-A, when administered intracerebroventricularly, retarded spatial learning. A probe test examined after training of water maze task also showed an impairment in spatial memory. The results of an electrophysiological study using hippocampal slices demonstrated that 1.0 to 30 nM of orexin-A applied to the perfusate produces a dose-dependent and time dependent suppression of the long-term potentiation. In addition, the long-term depression was not affected by orexin-A. The results of a paired-pulse facilitation experiment indicated that the effects of orexin-A were post-synaptic and not due to presynaptic transmitter release. These results show that orexin-A impairs spatial performance and these impairments can be attributed to a suppression of long-term potentiation in the Schaffer collateral-CA1 hippocampal synapses. [Copyright &y& Elsevier]

Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i) on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii) on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii) on randomly found dendritic shafts in str. oriens and iv) on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines.These results show that synaptic NMDA receptor density differs between pyramidal cells and interneurons. Some interneurons may have a high NMDA receptor content, whereas others, like some parvalbumin-expressing cells, a particularly low synaptic NMDA receptor content. Consequently, fast glutamatergic activation of interneurons is expected to show cell type-specific time course and state-dependent dynamics. [Copyright &y& Elsevier]

Synaptic plasticity in the dentate gyrus is dependent on activation of the N-methyl-d-aspartate (NMDA)-subtype of glutamate receptors. In this study, we show that synaptic plasticity in turn regulates NMDA receptors, since subunits of the NMDA receptor complex are bidirectionally and independently regulated in the dentate gyrus following activation of perforant synapses in awake animals. Low-frequency stimulation that produced a mild synaptic depression resulted in a decrease in the NMDA receptor subunits NR1 and NR2B 48 h following stimulation. High-frequency stimulation that produced long-term potentiation resulted in an increase in NR1 and NR2B at the same time point. Further investigations revealed that in contrast to NR2B, NR1 levels increased gradually after long-term potentiation induction, reaching a peak level at 48 h, and were insensitive to the competitive NMDA receptor antagonist 3-3(2-carboxypiperazin-4-yl) propyl-1-phosphate. The increased levels of NR1 and NR2B at 48 h were found associated with synaptic membranes and with increased NMDA receptor-associated proteins, postsynaptic density protein 95, neuronal nitric oxide synthase and Ca2+/calmodulin-dependent protein kinase II, α subunit. These data suggest that the persistence of long-term potentiation is associated with an increase in the number of NMDA receptor complexes, which may be indicative of an increase in synaptic contact area. [Copyright &y& Elsevier]

Recent evidence has emphasised the importance of mitogen-activated protein kinase activation in the modulation of hippocampal synaptic plasticity. Whilst extracellular-regulated kinase activation is now regarded as a critical step in the induction of long-term potentiation (LTP), activation of p38 and c-Jun N-terminal kinase (JNK) is associated with its inhibition. Here, the effects of the novel JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-1 (SP600125) were investigated on the inhibition of LTP by cytokines interleukin-1β, interleukin-18 and tumour necrosis factor-α in the dentate gyrus. Perfusion of SP600125 alone prior to tetanic stimulation of the medial perforant path did not significantly affect baseline synaptic transmission, post-tetanic potentiation or the magnitude of induced LTP. When SP600125 was perfused onto slices prior to application of cytokines, this resulted in a complete reversal of the cytokine-mediated inhibition of LTP. Moreover, the magnitude of LTP attained in these slices was significantly greater than that obtained in vehicle control slices. Next, we investigated the effects of the JNK inhibitor on the impairment of pharmacologically isolated N-methyl-D-aspartate receptor-mediated potentials (NMDA-EPSPs) by interleukin-18. Whilst not affecting baseline amplitude when perfused alone, prior perfusion of SP600125 alleviated the depressive effect of interleukin-18 on NMDA-EPSPs. Finally, we examined the possibility of JNK involvement in the induction of long-term depression (LTD) in the dentate gyrus. Perfusion of SP600125 prior to low-frequency stimulation of the perforant path resulted in a significant attenuation of induced LTD, which suggests that JNK activation is a critical mediator of LTD in the dentate gyrus.These results directly implicate, for the first time, differential activation of JNK in the modulation of distinct forms of hippocampal synaptic plasticity. Whereas acute over-activation of JNK by pathophysiological concentrations of cytokines is detrimental to LTP, physiologic activation of JNK appears necessary for the induction of LTD. [Copyright &y& Elsevier]

Amyloid-β precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-β (Aβ) peptide found in neuritic plaques of Alzheimer’s disease (AD) patients. Because Aβ shows neurotoxic properties, and because familial forms of AD promote Aβ accumulation, a massive international research effort has been aimed at understanding the mechanisms of Aβ generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPα (sAPPα), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Aβ appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Aβ, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Aβ, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease. [Copyright &y& Elsevier]

It is only recently that a number of studies on synaptic plasticity in the hippocampus and other brain areas have considered that a heterosynaptic modulatory input could be recruited as well as the coincident firing of pre- and post-synaptic neurons. So far, the strongest evidence for such a regulation has been attributed to dopaminergic (DA) systems but other modulatory pathways have also been considered to influence synaptic plasticity. This review will focus on dopamine contribution to synaptic plasticity in different brain areas (hippocampus, striatum and prefrontal cortex) with, for each region, a few lines on the distribution of DA projections and receptors. New insights into the possible mechanisms underlying these plastic changes will be considered. The contribution of various DA systems in certain forms of learning and memory will be reviewed with recent advances supporting the hypothesis of similar cellular mechanisms underlying DA regulation of synaptic plasticity and memory processes in which the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway has a potential role. To summarize, endogenous DA, which depends on the activity patterns of DA midbrain neurons in freely moving animals, appears as a key regulator in specific synaptic changes observed at certain stages of learning and memory and of synaptic plasticity. [Copyright &y& Elsevier]

To investigate the role in synaptic plasticity of Ca2+ released from intracellular Ca2+ stores, mice lacking the inositol 1,4,5-trisphosphate type 1 receptor were developed and the physiological properties, long-term potentiation, and long-term depression of their hippocampal CA1 neurons were examined. There were no significant differences in basic synaptic functions, such as membrane properties and the input/output relationship, between homozygote mutant and wild-type mice. Enhanced paired-pulse facilitation at interpulse intervals of less than 60 ms and enhanced post-tetanic potentiation were observed in the mutant mice, suggesting that the presynaptic mechanism was altered by the absence of the inositol 1,4,5-trisphosphate type 1 receptor. Long-term potentiation in the field-excitatory postsynaptic potentials induced by tetanus (100 Hz, 1 s) and the excitatory postsynaptic currents induced by paired stimulation in hippocampal CA1 pyramidal neurons under whole-cell clamp conditions were significantly greater in mutant mice than in wild-type mice. Homosynaptic long-term depression of CA1 synaptic responses induced by low-frequency stimulation (1 Hz, 500 pulses) was not significantly different, but heterosynaptic depression of the non-associated pathway induced by tetanus was blocked in the mutant mice. Both long-term potentiation and long-term depression in mutant mice were completely dependent on N-methyl-d-aspartate receptor activity. To rule out the possibility of an effect compensating for the lack of the inositol 1,4,5-trisphosphate type 1 receptor occurring during development, an anti-inositol 1,4,5-trisphosphate type 1 receptor monoclonal antibody that blocks receptor function was diffused into the wild-type cell through a patch pipette, and the effect of acute block of inositol 1,4,5-trisphosphate type 1 receptor on long-term potentiation was examined. Significant enhancement of long-term potentiation was observed compared with after control immunoglobulin G injection, suggesting that developmental redundancy was not responsible for the increase in long-term potentiation amplitude observed in the mutant mouse. The properties of channels that could be involved in long-term potentiation induction were examined using whole-cell recording. N-methyl-d-aspartate currents were significantly larger in mutant mice than in wild-type mice only between holding potentials of −60 and −80 mV. We conclude that inositol 1,4,5-trisphosphate type 1 receptor activity is not essential for the induction of synaptic plasticity in hippocampal CA1 neurons, but appears to negatively regulate long-term potentiation induction by mild modulation of channel activities. [Copyright &y& Elsevier]

The mode of action of the antipsychotic drugs clozapine, haloperidol and iloperidone was investigated in layer V of prefrontal cortex slices using extracellular field potential, intracellular sharp-electrode as well as whole-cell voltage clamp recording techniques. Intracellular investigations on a broad range of concentrations revealed that the typical neuroleptic haloperidol at higher concentrations significantly depressed the excitatory postsynaptic component induced by electrical stimulation of layer II. This was not seen with the atypical neuroleptics clozapine and iloperidone. None of the three compounds had any effect on the resting membrane potential, spike amplitude or input resistance at relevant concentrations. Synaptic plasticity was assessed by means of extracellular field potential recordings. Clozapine significantly facilitated the potentiation of synaptic transmission, whereas haloperidol and iloperidone showed no effects. In line with its facilitating effect on synaptic plasticity, it could be demonstrated by whole-cell voltage clamp recordings that clozapine increased N-methyl-D-aspartic acid receptor-mediated excitatory postsynaptic currents in the majority of prefrontal cortical neurones. These investigations were made with neuroleptic drugs applied to the bath in the micromolar concentration range in order to approach clinical brain concentrations that are reached after administration of therapeutic doses. The drug concentrations reached in the slices after the experiments were assessed by means of high-pressure liquid chromatography coupled with mass-spectrometric detection. Surprisingly, drug accumulation in the in vitro preparation was of similar degree as reported in vivo.In conclusion, the typical neuroleptic haloperidol significantly depressed excitatory synaptic transmission in layer V neurones of the prefrontal cortex. In contrast, the two atypical neuroleptics iloperidone and clozapine revealed no depressing effects. This feature of the atypical neuroleptics might be beneficial since a hypofunctionality of this brain area is thought to be linked with the pathophysiology of schizophrenia. Additionally, clozapine facilitated long-term potentiation, which might be linked with the clinically observed beneficial effects on certain cognitive parameters. The clozapine-induced increase of N-methyl-D-aspartic acid receptor-mediated currents suggests that clozapine facilitates the induction of long-term potentiation. Furthermore, the present study points to the importance of considering the significant accumulation of neuroleptic drugs in in vitro studies. [Copyright &y& Elsevier]

Recent advances have been made in understanding the changes in neuronal plasticity in psychiatric disease at the molecular level (changes in neurotransmission, long-term potentiation, long-term depression, glutamate receptors, synaptic strength and neurotrophic support) and the systems level (changes in hippocampal, frontal and amygdala function in health and disease and the impact of stress on the hippocampal/frontal axis), as well as in the impact of drugs and sites of action for therapeutic intervention. Drugs acting on plasticity could affect the abnormal set point in psychiatric disease, resulting in treatment of the disease rather than just the symptoms. [Copyright &y& Elsevier]

The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-d-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system. [Copyright &y& Elsevier]

Polysialic acid is a unique carbohydrate composed of a linear homopolymer of α2,8-linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) via a typical N-linked glycan in vertebrate neural system. Polysialic acid plays critical roles in neural development by modulating adhesive property of NCAM such as neural cell migration, neurite outgrowth, neural pathfinding, and synaptogenesis. The expression of polysialic acid is temporally and spatially regulated during neural development. Polysialylation of NCAM is catalyzed by two polysialyltransferases, ST8Sia II (STX) and ST8Sia IV (PST), which belong to the family of six genes encoding α2,8-sialyltransferases. ST8Sia II and IV are expressed differentially in tissue-specific and cell-specific manners, and they apparently have distinct roles in development and organogenesis. The presence of polysialic acid is always associated with expression of ST8Sia II and/or IV, suggesting that ST8Sia II and IV are the key enzymes that control the expression of polysialic acid. Both ST8Sia II and IV can transfer multiple α2,8-linked sialic acid residues to an acceptor N-glycan containing a NeuNAcα2→3 (or 6) Galβ1→4GlcNAcβ1→R structure without participation of other enzymes. The two enzymes differently but cooperatively act on NCAM and the amount of polysialic acid synthesized by both enzymes together is greater than that synthesized by either enzyme alone. The polysialyltransferases are thus important regulators in polysialic acid synthesis and contribute to neural development in the vertebrate. [Copyright &y& Elsevier]

The N-methyl-d-aspartate (NMDA) receptor is an example of a heteromeric ligand-gated ion channel that interacts with multiple intracellular proteins by way of different subunits. NMDA receptors are composed of seven known subunits (NR1, NR2A–D, NR3A–B). The present review focuses on the NR2B subunit of the receptor. Over the last several years, an increasing number of reports have demonstrated the importance of the NR2B subunit in a variety of synaptic signaling events and protein-protein interactions. The NR2B subunit has been implicated in modulating functions such as learning, memory processing, pain perception, and feeding behaviors, as well as being involved in a number of human disorders. The following review provides a summary of recent findings regarding the structural features, localization, functional properties, and regulation of the NR2B subunit. The review concludes with a section discussing the role of NR2B in human diseases. [Copyright &y& Elsevier]

Aluminium (Al), has the potential to be neurotoxic in humans and animals, and is present in many manufactured foods and medicines and is also added to drinking water for purification purposes. Our previous study demonstrated that chronic Al exposure induced deficits of both long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic potential (EPSP) and population spike (PS) in rat dentate gyrus (DG) of hippocampus in vivo (Wang et al., 2001). The purpose of the present study was to investigate whether the Al-induced impairment of synaptic plasticity could be reversed by dietary supplementation with vitamin E (Vit E; α-tocopherol). Neonatal Wistar rats were exposed to Al from parturition throughout life by drinking 0.3% aluminium chloride (AlCl3) solution or a diet supplemented with Vit E at 500 μg/g/day with 0.3% AlCl3. The input/output (I/O) function, EPSP and PS were measured in DG area of adult rats (80–100 days of age) in response to stimulation applied to the lateral perforant path. The results showed that: (1) chronic Al exposure reduced the amplitudes of both EPSP LTP (control: 130.4±3%, n=7; Al-exposed: 110±2%, n=9, P<0.001) and PS LTP (control: 241±19%, n=7; Al-exposed: 130±7%, n=9, P<0.001) significantly. Vit E had no significant effects on the Al-induced deficits of EPSP LTP (Al-exposed: 110±2%, n=9; Al-exposed+Vit E: 112±2%, n=8, P>0.05) and PS LTP (Al-exposed: 130±7%, n=9; Al-exposed+Vit E: 129±4%, n=8; P>0.05); (2) the amplitudes of EPSP LTD (control: 84±4%, n=7; Al-exposed: 92±7%, n=9, P<0.01) and PS LTD (control: 81±4%, n=7; Al-exposed: 98±5%, n=9, P<0.001) were also decreased by Al treatment. The impaired EPSP LTD (Al-exposed: 92±7%, n=9; Al-exposed+Vit E: 93±4%, n=8, P>0.05) and PS LTD (Al-exposed: 98±5%, n=9; Al-exposed+Vit E: 94±6%, n=8, P>0.05) were also not significantly affected by Vit E treatment. It was suggested that dietary supplementation with Vit E did not reverse the impairment of synaptic plasticity induced by Al in DG in vivo. [ABSTRACT FROM AUTHOR]

Phospholipase A2 (PLA2) activation generates the release of arachidonic acid (AA) and platelet-activating factor (PAF), two compounds which may be involved in neuroplasticity. In previous studies, we found that PLA2 activation is involved in the development of stimulant sensitization. In the present study, we have examined the roles of AA and PAF in the development of stimulant sensitization using agonists and antagonists selective for PAF receptors or the induction of various AA cascade-mediated eicosanoids. Sprague–Dawley rats were treated for 5 days with cocaine (30 mg/kg) or d-amphetamine (1 mg/kg) preceded 15 min earlier by various antagonists, and then tested following a 10-day withdrawal period for cocaine (15 mg/kg) or d-amphetamine (0.5 mg/kg)-induced locomotion. Consistent with our earlier work, pretreatment with the PLA2 inhibitor quinacrine (25 mg/kg) blocked the development of cocaine and amphetamine sensitization. The lipoxygenase (LOX) inhibitors nordihydroguaiaretic acid (NDGA) (5–10 mg/kg) and MK-886 (1 mg/kg) had no effect on cocaine sensitization. The PAF receptor antagonist WEB 2086 (5–10 mg/kg) reduced the development of cocaine sensitization. The cyclooxygenase (COX) inhibitors indomethacin (1–2 mg/kg), piroxicam (0.5–1 mg/kg), 6-methoxy-2-napthylacetic acid (6-MNA; 0.5–1 mg/kg), and NS-398 (0.5–1 mg/kg) blocked the development of cocaine sensitization. The COX inhibitors indomethacin (2 mg/kg) and 6-MNA (1 mg/kg) also reduced the development of amphetamine sensitization. Rats were administered bilateral intraventral tegmental area (VTA) injections of d-amphetamine (5 μg/side) or saline coadministered with indomethacin (0.5 μg/side) or vehicle three times over 5 days and were then tested after a 10-day withdrawal for d-amphetamine (0.5 mg/kg ip)-induced locomotion. Intra-VTA amphetamine induced a robust form of amphetamine sensitization, which was blocked by coadministration of indomethacin. Unilateral intra-VTA injections of PAF (1 μg) did not significantly alter cocaine (15 mg/kg ip)-induced locomotion when tested after a 3-day withdrawal. These findings suggest that COX, and possibly PAF, activity is involved in the development of stimulant sensitization. Neuroanatomical studies demonstrate that this may occur at the level of the VTA. [Copyright &y& Elsevier]