Zinc is a trace element which plays a fundamental role in a wide range of biochemical processes in living organisms. Zinc is an essential component of various proteins and is an important factor for physiological function of the mammalian nervous and immune systems. In the central nervous system (CNS), zinc is found at high concentrations in hippocampal neurons. These neurons possess mechanisms for zinc uptake and storage in synaptic terminals and for the stimulation of zinc release along with neurotransmitters. In the central nervous system, zinc modulates predominantly the excitatory (glutamatergic) and inhibitory (GABAergic) amino acid neurotransmission pathways. In the immune system, zinc is necessary for the physiological activity of the thymus and T-cell-dependent responses. Zinc deficiency impairs the activities of the neuroendocrine and immune systems in mammalian organisms. This paper reviews the alterations in the blood and brain zinc concentrations in relation to the neuroimmune pathophysiology and treatment of depression. Major depression is related to lowered serum zinc concentrations, which may be caused by the acute phase and the inflammatory response in that illness. Repeated administration of antidepressants selectively increases and redistributes brain zinc in the hippocampus. Since zinc is an inhibitor of the glutama-te/NMDA receptor, these data are in accordance with the glutamate hypothesis of antidepressant action.

We present the case of a 25-year-old woman who initially presented after committing an assault resulting in serious injury. She exhibited recent onset psychiatric symptoms which were later followed by a rapid deterioration in her physical health. She was treated with electroconvulsive therapy on a medical intensive care unit for a presumptive diagnosis of malignant catatonia. A test for anti-NMDA receptor antibodies returned positive. She was treated with IV immunoglobulin (IVIg) and high dose steroids, then underwent a left ovarian cystectomy. She was subsequently treated on a psychiatric intensive care unit until discharge.

In the South African clawed-toed frog Xenopus laevis, visual experience plays a crucial role in the formation of matching binocular maps in the tectum. The ipsilateral eye's projection, relayed through the crossed isthmotectal projection, displays marked plasticity in response to altered visual input during a critical period of development. This plasticity and the events responsible for the end of the critical period are mediated by N-methyl-D-aspartate (NMDA) receptor function. We have previously reported that chronic blockade of tectal NMDA receptors with the NMDA antagonist 5-amino-phosphonovaleric acid (APV) prevents plasticity of the crossed isthmotectal projection during the critical period, while chronic treatment with NMDA restores this plasticity after the end of the critical period. These results raise the question of whether the effects on plasticity are due to changes in electrical responsiveness of the treated tissue. In this study, we have quantitatively assessed the actions of APV and NMDA on certain aspects of tectal cell activity in Xenopus during and after the critical period by recording the output of the nucleus isthmi cells that are activated by the tectum after three weeks of treatment. We have found that chronic APV treatment does not alter tectal output, as indicated by the firing of isthmotectal axons, during the critical period and that chronic NMDA treatment increases tectal output in postcritical period Xenopus. Tectal output does not differ between normal Xenopus during and after the end of the critical period.

These results indicate that the effect of APV on blocking isthmotectal plasticity is not due to a nonspecific inhibition of the segment of the retinotectal relay that activates the nucleus isthmi. The enhancement of tectal output in postcritical period Xenopus by chronic NMDA treatment may promote the effectiveness of NMDA in restoring isthmotectal plasticity after the end of the critical period, but the finding that tectal activity does not differ between normal Xenopus during and after the critical period implies that a reduction in tectal activity in not the cause of the loss of plasticity at the end of the critical period.

The passive electrical properties of 17 ON-OFF retinal ganglion cells were derived from electrophysiological recordings. The parameters for each cells' equivalent model were obtained from the transient current responses to small step changes in clamp potential. Thirteen of the cells could be adequately approximated by a spherical soma connected to an equivalent dendritic cable. Estimates for the cell input conductance (GN), membrane time constant (τm), the dendritic-to-soma conductance ratio (ρ), and the normalized electrotonic length (L) were obtained (mean ± standard deviation, n = 13): GN = 580 ± 530 pS, τm = 97 ±72 ms, ρ = 2.8 ± 2.8, and L = 0.34 ± 0.13. Series resistance averaged 32 ± 11 MΩ The mean of the derived soma diameters was 18 ± 6 μm and the mean diameter and length of the equivalent cables were 1.4 ± 0.6 and 470 ± 90 μm, respectively. The average of the specific membrane conductances, 1.67 ± 1.08 S/cm2, corresponded to a membrane resistivity of 60 kΩ-cm2. Computer simulations of synaptic inputs were performed on a representative model, with an electrode at the soma and using the worst-case configuration, in which all synaptic inputs were confined to the tips of the dendrites. We draw three conclusions from the modeling: (1) Under voltage clamp, fast, spontaneous EPSCs would be significantly attenuated and slowed while the time course of the slower, light-evoked non-NMDA and NMDA EPSCs would be minimally distorted by dendritic filtering. (2) Excitatory synaptic reversal potentials can be accurately determined under voltage clamp. (3) In the absence of GABAergic and glycinergic inhibition, the efficacy at the soma of excitatory conductance changes is essentially independent of their dendritic location. The specific membrane resistivity appears to represent a good compromise between having a small membrane time constant and minimal EPSP attenuation.

In visual neurones of the superficial layers of the superior colliculus (SSC), repetitive stimulation causes a progressive decline in the size of the response to the stimulus, usually known as response habituation or response adaptation. A mechanism has been proposed in which habituation results from coactivation of excitatory and inhibitory neurones, and the responses of the inhibitory neurones block the response to subsequent stimulus presentations. Excitatory amino acid (EAA) neurotransmitters mediate visual responses via NMDA and non-NMDA receptors in cat SSC. We have investigated the role of these receptors in the generation of response habituation. Following the iontophoretic application of the EAA antagonists CNQX, APS or CPP, repetitive visual stimulation paradigms which normally produce response habituation no longer do so. Indeed the response to each presentation of the stimulus is similar. Intravenous administration of the dissociative anesthetic ketamine (2–10 mg/kg) had similar actions to iontophoretically applied NMDA antagonists. The data imply that intracollicular mechanisms activated by NMDA and non-NMDA receptors contribute to the generation of the inhibitory responses in SCC which lead to response habituation. Furthermore, the effects seen with ketamine anesthesia suggest that the use of ketamine in studies of sensory systems may result in the lack of habituation.

In this double-blind, placebo-controlled study, we examined the effects of subanaesthetic doses of ketamine (an NMDA glutamate receptor antagonist) and thiopental (a GABA-A receptor agonist) on the event-related potential (ERP) correlates of deviant stimulus processing in 24 healthy adults. Participants completed three separate pharmacological challenge sessions (ketamine, thiopental, saline) in a counterbalanced order. EEG data were recorded both before and during each challenge while participants performed a visual ‘oddball’ task consisting of infrequent ‘target’ and ‘novel’ stimuli intermixed with frequent ‘standard’ stimuli. We examined drug effects on the amplitude and latency of the P300 (P3) component of the ERP elicited by target (P3b) and novel stimuli (P3a), as well as the N200 (N2) component elicited by both target and novel stimuli, and the N100 (N1) elicited by standard stimuli. Relative to placebo, both drugs reduced the amplitude of parietal P3b. While both drugs reduced parietal P3a and Novelty N2, ketamine also shortened P3a latency, reduced Novelty N2 amplitude more than thiopental, and increased frontal P3a amplitude relative to placebo. Overall, the data suggest that both the GABA-A and NMDA receptor systems modulate P3b and P3a. NMDA antagonism appears to lead to more varied effects on the neural correlates of novelty processing.

Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.

ABSTRACT

Background: There is a great need to develop new antipsychotic agents. In addition to dopaminergic neurotransmission, glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia. The most compelling link between glutamatergic N-methyl-d-aspartate (NMDA) neurotransmission and schizophrenia concerns the mechanism of action of the psychotomimetic drug phencyclidine and the dissociative anesthetic, ketamine; both are NMDA antagonists. The psychosis induced by the NMDA antagonists causes not only positive symptoms similar to the action of dopaminergic enhancers but also negative symptoms and cognitive deficits typical of schizophrenia in normal volunteers and worsening of the psychotic symptoms in patients with schizophrenia. Accordingly, enhancing NMDA neurotransmission should benefit the symptoms of schizophrenia. Methods: Most clinical trials were done by the addition of the NMDA-enhancing agents, glycine, d-serine, d-alanine, d-cycloserine and sarcosine to the stable regimens of antipsychotics in double-blind, placebo-controlled designs. Results: When taken together, the trials of NMDA-enhancing agents in patients with chronic schizophrenia receiving stable dose of antipsychotics, the NMDA-enhancing agents were effective in the domains of negative symptoms, cognition, depression, positive symptoms and general psychopathology. The agents also significantly improved extrapyramidal symptoms. No significant side-effects or safety concerns emerged. Interpretation: In addition to testing more lead compounds, dose-finding and long-term trials are required to determine the optimal dose and functional improvement capacity of NMDA receptor agonist. The agents may also be applied to prevention and the treatment for prodromal phases of the illness.

The transcriptional mechanisms that govern the development and plasticity of somatopic sensory maps in the cerebral cortex have not been studied extensively. In particular, no studies have addressed the role of epigenetic mechanisms in the development of sensory maps. DNA methylation is one of the main epigenetic mechanisms by which mammalian cells regulate gene transcription. Demethylation results in embryonic lethality, so it has been very difficult to study the role of DNA methylation in brain development. We have used cre-loxP technology to generate forebrain-specific deletion of DNA methyltransferase 1 (Dnmt1), the enzyme required for the maintenance of DNA methylation. We find that DNA hypomethylation of neurons in the cerebral cortex results in the failure of development of somatosensory barrel cortex. We also find that, despite functional thalamocortical neurotransmission, thalamocortical long-term potentiation cannot be induced in slices from Emx1-cre;Dnmt1 mutant mice. These studies emphasize the importance of DNA methylation for the development of sensory maps and indicate that epigenetic mechanisms might play a role in the development of synaptic plasticity.

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3β activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including β-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.

When normal binocular visual experience is disrupted during postnatal development, it affects the maturation of cortical circuits and often results in the development of poor visual acuity known as amblyopia. Two main factors contribute to the development of amblyopia: visual deprivation and reduced binocular competition. We investigated the affect of these two amblyogenic factors on the expression of the NMDAR1 subunit in the visual cortex because activation of the NMDA receptor is a key mechanism of developmental neural plasticity. We found that disruption of binocular correlations by monocular deprivation promoted a topographic loss of NMDAR1 expression within the cortical representations of the central visual field and the vertical and horizontal meridians. In contrast, binocular deprivation, which primarily affects visual deprivation, promoted an increase in NMDAR1 expression throughout the visual cortex. These different changes in NMDAR1 expression can be described as topographic and homeostatic plasticity of NMDA expression, respectively. In addition, the changes in NMDA expression in the visual cortex provide a greater understanding of the neural mechanisms that underlie the development of amblyopia and the potential for visual recovery.

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl-D-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc.

Application of NMDA induces a depolarization and increase of intracellular calcium concentration ([Ca2+]i) in retinal ganglion cells, which cause ganglion cell death in models of glaucoma. In the present study, we investigated the pharmacological mechanism of how NMDA-evoked increase in calcium could be modulated in dissociated retinal ganglion cells from tiger salamander. In these neurons, protein kinase A (PKA) up-regulated the NMDA-evoked [Ca2+]i increase. In the presence of 8-bromo-cAMP or forskolin to stimulate PKA, the elevation level of [Ca2+]i induced by NMDA became even higher; In the presence of H-89, a PKA inhibitor, the NMDA-evoked [Ca2+]i increase was attenuated. In addition, applications of adrenergic compounds were also found to influence the NMDA-evoked [Ca2+]i increase. UK-14,304, a selective α2 agonist, reduced the elevation level of [Ca2+]i caused by NMDA. In contrast, isoproterenol, a β agonist, augmented the NMDA-evoked [Ca2+]i increase. These adrenergic regulations were due to direct activation of adrenoceptors, since modulations of both UK-14,304 and isoproterenol on the NMDA-evoked [Ca2+]i increase were abolished by their respective antagonists. Furthermore, adrenergic regulations were mediated through a PKA-related pathway since PKA inhibitor blocked adrenergic regulations. The possible modulatory site(s) by PKA was also discussed.

The interaction between cortical input frequency and intrinsic thalamic neuron (TN) properties were investigated using intracellular recordings from mice TNs in thalamocortical (TC) slices. Excitatory postsynaptic potentials (EPSPs) of corticothalamic (CT) origin were recorded at TN membrane potentials (Vm) held, by current clamp means, between −59 and −55 mV to avoid low-threshold calcium currents (IT) activation. EPSPs elicited in ventrobasal neurons (n = 25) by stimulation in the internal capsule showed constant latency, relatively fast rise time (2.9 ± 0.56 ms) and short duration (26.6 ± 9.11 ms). EPSPs evoked by threshold stimulation (n = 10) showed similar characteristics (mean rise time, 2.74 ± 0.42 ms; mean duration, 30 ± 8.00 ms). The time course of CT synaptic facilitation was determined using pairs of stimuli. Paired-pulse facilitation (PPF) of CT EPSPs peaked at 25–30 ms stimulus intervals and decayed exponentially with an average time constant of 130 ms (n = 50). Application of the NMDA receptor blocker APV (25 μM, n = 4) did not modify PPF for any interstimulus interval studied but suppressed frequency facilitation evoked by trains of CT stimuli. We compared the number of spikes per stimulus (Fs) evoked in TNs by repetitive CT stimulation over a range of frequencies at different Vm. At hyperpolarized Vm (below −65 mV) and frequencies of stimulation ≥ 10 Hz, Fs decreased along the train while at depolarized Vm (above −59 mV) Fs increased along the train. Decremental patterns resulted from the activation of IT while facilitatory patterns emerged from superposition of synaptic and intrinsic mechanisms. At hyperpolarized Vm, steady-state Fs was maximal for frequencies ≤ 2 Hz, intermediate for frequencies between 2 and 10 Hz and zero at ≥ 10 Hz. At depolarized Vm, steady-state Fs increased with increasing frequencies (from 1 to 40 Hz).

We conclude that the CT–TN junctions are tuned to establish stable thalamocortical resonant dynamics.

It has been previously demonstrated that the majority of the glutamatergic input to directionally selective (DS) ganglion cells in the rabbit retina is mediated by NMDA receptors. To examine whether NMDA channels have any role in directional selectivity, we eliminated magnesium from the superfusion medium to prevent the magnesium block of the channels at hyperpolarized membrane potentials. During superfusion in magnesium-free media, the response to null-direction motion increased to the level of the response to preferred-direction motion. This effect was specifically mediated by NMDA channels because subsequent blocking of the NMDA channels with AP7 restored directional selectivity. We also tested whether the increase in the null-direction response in magnesium-free medium was due to an increased release of acetylcholine from the cholinergic amacrine cells, rather than an effect on the DS ganglion cells themselves, by blocking acetylcholine transmission with d-tubocurarine during superfusion with the magnesium-free medium. During zero-magnesium superfusion, d-tubocurarine reduced both the preferred- and null-direction responses of DS ganglion cells but did not restore directional selectivity. These findings suggest that null-direction motion normally causes portions of the dendritic membrane of the directionally selective ganglion cell to be maintained at a sufficiently negative potential that the NMDA channels are blocked by magnesium ions. This result is discussed in terms of several models for the mechanisms of directional selectivity.

Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with “Hebbian” descriptions of memory formation. Other characteristics of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms, provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism.