Background: Carbon monoxide (CO) poisoning is the leading cause of accidental poisoning worldwide. This study undertook a meta-analysis to examine differences in neuropsychological functioning in patients with CO poisoning as compared to healthy controls, and examined the longer-term neuropsychological effects of CO poisoning. Methods: Studies performed between the years 1995 and 2016 were identified through a search of the electronic databases Medline and PsycInfo. Data from the papers identified were pooled to determine standard mean differences using a random-effects model. Results: Ten studies were included in the analysis, with healthy controls performing significantly better than CO poisoned participants on the domains of divided attention, immediate memory, and processing speed. No statistically significant differences were found for sustained attention, recent memory, working memory, visuospatial/constructional ability, and expressive language. Performance by participants with CO poisoning for the domains of sustained attention, recent memory, visuospatial/constructional abilities, and working memory significantly improved over time after initial exposure, demonstrating recovery of these functions over time. No statistically significant differences were evident for divided attention or expressive language. Conclusions: This evidence indicates that healthy controls perform better than do individuals with CO poisoning on a range of neuropsychological domains; however, it also indicates that performance in some domains does improve over time. (JINS, 2018, 24, 405–415)

Natural bornavirus infections and their resulting diseases are largely restricted to horses and sheep in Central Europe. The disease also occurs naturally in cats, and can be induced experimentally in laboratory rodents and numerous other mammals. Borna disease virus-1 (BoDV-1), the cause of most cases of mammalian Borna disease, is a negative-stranded RNA virus that replicates within the nucleus of target cells. It causes severe, often lethal, encephalitis in susceptible species. Recent events, especially the discovery of numerous new species of bornaviruses in birds and a report of an acute, lethal bornaviral encephalitis in humans, apparently acquired from squirrels, have revived interest in this remarkable family of viruses. The clinical manifestations of the bornaviral diseases are highly variable. Thus, in addition to acute lethal encephalitis, they can cause persistent neurologic disease associated with diverse behavioral changes. They also cause a severe retinitis resulting in blindness. In this review, we discuss both the pathological lesions observed in mammalian bornaviral disease and the complex pathogenesis of the neurologic disease. Thus infected neurons may be destroyed by T-cell-mediated cytotoxicity. They may die as a result of excessive inflammatory cytokine release from microglia. They may also die as a result of a ‘glutaminergic storm’ due to a failure of infected astrocytes to regulate brain glutamate levels.

This article describes the use of non-invasive magnetic resonance (MR) methods for the characterization and monitoring of the pathophysiology of experimental brain injury in laboratory animals as a function of time and treatment. The impact of MR in brain research is primarily due to its non-invasive nature, thereby enabling repeated measurements in long-term studies, and due to the type of information that it provides. MR imaging (MRI) enables the measurement of the morphology/anatomy as well as the functional status of tissues under in vivo conditions. Compared to other in vivo imaging modalities, MRI has a high spatial resolution and allows for a remarkable soft tissue differentiation. MR spectroscopy (MRS) provides information on the biochemical/metabolic status of tissues. MR methods which have proven valuable in animal studies, can be readily translated to the clinical situation where MR-based diagnosis and treatment planning play a rapidly increasing role.

After a short introduction into the principles of MR, we will illustrate the remarkable versatility of MR in research on brain injury from recent animal studies. Examples will be mainly drawn from experiments on early injury in focal cerebral ischemia and from research on mechanical brain trauma and excitotoxic lesions. The article ends with a brief description of the perspectives of MR in neuropsychiatry.

Cerebral white matter injury in premature infants, known as periventricular leukomalacia (PVL), is common after hypoxia–ischemia (HI). While ionotropic glutamate receptors (iGluRs) can mediate immature white matter injury, we have previously shown that excitotoxic injury to premyelinating oligodendrocytes (preOLs) in vitro can be attenuated by group I metabotropic glutamate receptor (mGluR) agonists. Thus, we evaluated mGluR expression in developing white matter in rat and human brain, and tested the protective efficacy of a central nervous system (CNS)-penetrating mGluR agonist on injury to developing oligodendrocytes (OLs) in vivo. Group I mGluRs (mGluR1 and mGluR5) were strongly expressed on OLs in neonatal rodent cerebral white matter throughout normal development, with highest expression early in development on preOLs. Specifically at P6, mGluR1 and mGLuR5 were most highly expressed on GalC-positive OLs compared to neurons, axons, astrocytes and microglia. Systemic administration of (1S,3R) 1-aminocyclopentane-trans-1,3,-dicarboxylic acid (ACPD) significantly attenuated the loss of myelin basic protein in the white matter following HI in P6 rats. Assessment of postmortem human tissue showed both mGluR1 and mGluR5 localized on immature OLs in white matter throughout development, with mGluR5 highest in the preterm period. These data indicate group I mGluRs are highly expressed on OLs during the peak period of vulnerability to HI and modulation of mGluRs is protective in a rodent model of PVL. Group I mGluRs may represent important therapeutic targets for protection from HI-mediated white matter injury.

The present study examines the differential effects of three excitotoxins, kainic acid (KA), N-methyl-D-aspartate (NMDA), and α-amino-2,3-amino-2,3-dihydro-5- methyl-3-oxo-4- isoxazolepropanoic acid (AMPA) on neurons within the genglion cell layer (GCL) of the chick retina. Two-day-old chicks were given a single, 5 μl, intravitreal injection of KA, NMDA, or AMPA at a range of doses. Following treatment with 40 nmol KA, there was a 21% loss of neurons in the GCL. At 200 nmol KA, the loss increased to 46%. Exposure to KA eliminated mainly small neurons of soma area 5–15μm2, and medium-sized ganglion cells of soma area 15–25μm2. Large ganglion cells (>25μ,2) remained unaffected. The vast majority of small cells were probably displaced amarcrine cells. At a does of 3000 nmol NMDA, no further loss of cells was evident. Exposure to 200 nmol AMPA resulted in a 30% loss of large and some medium-sized ganglion cells. In a further series of experiments, exposure to excitotoxin was followed by a retinal scratch, which eliminated retinal ganglion cells within the axotomized region. The results indicate that only a small proportion of displaced amacrine cells are destroyed by NMDA and AMPA, whereas virtually all displaced amarine cells are sensitive to KA. The findings of this study indicate the existence of subclasses of ganglion cells with specificity towards different types of excitatory amino acids (EAA).

Glutamate is the principal excitatory neurotransmitter in the CNS, but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on Ca2+ overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated either by AMPA/kainate antagonists or by the blockade of the system xc_ antiporter present in microglia. By contrast, non-lethal, brief, activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce Ca2+ overload of the cytosol and the generation of reactive oxygen species. In conjunction, these observations reveal novel mechanisms by which neuroinflammation alters glutamate homeostasis and triggers oligodendrocyte death. Conversely, they also show how glutamate signaling in oligodendrocytes might induce immune attack. In both instances direct activation of glutamate receptors present in oligodendrocytes plays a pivotal role in either initiating or executing death signals, which might be relevant to the pathogenesis of white matter disorders.

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.

Injury and disease in the CNS increases the amount of tumor necrosis factor α (TNFα) that neurons are exposed to. This cytokine is central to the inflammatory response that occurs after injury and during prolonged CNS disease, and contributes to the process of neuronal cell death. Previous studies have addressed how long-term apoptotic-signaling pathways that are initiated by TNFα might influence these processes, but the effects of inflammation on neurons and synaptic function in the timescale of minutes after exposure are largely unexplored. Our published studies examining the effect of TNFα on trafficking of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons demonstrate that glial-derived TNFα causes a rapid (<15 minute) increase in the number of neuronal, surface-localized, synaptic AMPARs leading to an increase in synaptic strength. This indicates that TNFα-signal transduction acts to facilitate increased surface localization of AMPARs from internal postsynaptic stores. Importantly, an excess of surface localized AMPARs might predispose the neuron to glutamate-mediated excitotoxicity and excessive intracellular calcium concentrations, leading to cell death. This suggests a new mechanism for excitotoxic TNFα-induced neuronal death that is initiated minutes after neurons are exposed to the products of the inflammatory response.

Here we review the importance of AMPAR trafficking in normal neuronal function and how abnormalities that are mediated by glial-derived cytokines such as TNFα can be central in causing neuronal disorders. We have further investigated the effects of TNFα on different neuronal cell types and present new data from cortical and hippocampal neurons in culture. Finally, we have expanded our investigation of the temporal profile of the action of this cytokine relevant to neuronal damage. We conclude that TNFα-mediated effects on AMPAR trafficking are common in diverse neuronal cell types and very rapid in their onset. The abnormal AMPAR trafficking elicited by TNFα might present a novel target to aid the development of new neuroprotective drugs.

We have examined the role of neighbor relationships between cholinergic amacrine cells upon their positioning and dendritic field size by producing partial ablations of this population of cells during early development. We first determined the effectiveness of l-glutamate as an excitotoxin for ablating cholinergic amacrine cells in the developing mouse retina. Subcutaneous injections (4 mg/g) made on P-3 and thereafter were found to produce a near-complete elimination, while injections at P-2 were ineffective. Lower doses on P-3 produced only partial reductions, and were subsequently used to examine the effect of partial ablation upon mosaic organization and dendritic growth of the remaining cells. Four different Voronoi-based measures of mosaic geometry were examined in l-glutamate-treated and normal (saline-treated) retinas. Partial depletions of around 40% produced cholinergic mosaics that, when scaled for density, approximated the mosaic geometry of the normal retina. Separate comparisons simulating a 40% random deletion of the normal retina produced mosaics that were no different from those experimentally depleted retinas. Consequently, no evidence was found for positional regulation in the absence of normal neighbor relationships. Single cells in the ganglion cell layer were intracellularly filled with Lucifer Yellow to examine the morphology and dendritic field extent following partial ablation of the cholinergic amacrine cells. No discernable effect was found on their starburst morphology, and total dendritic field area, number of primary dendrites, and branch frequency were not significantly different. Cholinergic amacrine cells normally increase their dendritic field area after P-3 in excess of retinal expansion; despite this, the present results show that this growth is not controlled by the density of neighboring processes.

Brain injury following cerebral ischaemia (stroke) involves a complex combination of pathological processes, including excitotoxicity and inflammation leading to necrotic and apoptotic forms of cell death. At the cellular level, excitotoxicity is mediated by glutamate and its cognate receptors, resulting in increased intracellular calcium and free radical production, and eventual cell death. Recent evidence suggests that scaffolding molecules that associate with glutamate receptors at the postsynaptic density allow coupling of receptor activity to specific second messengers capable of mediating excitotoxicity. These findings have important implications in the search for effective neuroprotective therapies in treating stroke.

Retinal ischemia, a major cause of visual loss, is believed to result from overexcitation of glutamate receptors. However, under euglycemic and normoxic conditions, exogenously applied glutamate is not neurotoxic in the retina. Under such conditions, exogenous glutamate typically causes glia swelling and requires very high concentrations to produce neurotoxicity. To determine whether ischemic conditions enhance the neurotoxicity of endogenous and exogenous glutamate, we examined the effects of simulated ischemia (deprivation of both glucose and oxygen) on retinal morphology and lactate dehydrogenase (LDH) release. In an ex vivo rat retinal preparation, glutamate was administered during simulated ischemia in the presence of riluzole, an inhibitor of glutamate release. Deprivation of both glucose and oxygen for 60 min at 30°C produced severe acute neurodegeneration. This neurodegeneration, characterized by bull's eye formation in the inner nuclear layer and spongy appearance in the inner plexiform layer, was prevented by the combination of MK-801 and DNQX, antagonists of N-methyl-D-aspartate (NMDA) and non-NMDA receptors, indicating that the damage results from activation of both glutamate receptors. We also found that administration of glutamate pyruvate transaminase (alanine aminotransaminase) with pyruvate diminished the neurodegeneration during simulated ischemia. Furthermore, riluzole, an inhibitor of glutamate release, attenuated the neurodegeneration, suggesting the importance of endogenous glutamate in ischemic damage. In the presence of riluzole and simulated ischemia, exogenously applied glutamate failed to cause Müller cell swelling but was extremely neurotoxic. These results suggest that simulated ischemia enhances glutamate-mediated neurotoxicity in part by depressing glutamate uptake. When glutamate transport is impaired, sub-millimolar glutamate concentrations become profoundly neurotoxic.

Photoreceptors in the ferret's retina have been shown to project transiently to the inner plexiform layer (IPL) prior to their differentiation of an outer segment. On postnatal day 15 (P-15), when this projection achieves maximal density, the photoreceptors projecting into the IPL extend primarily to one of two depths, coincident with the processes of cholinergic amacrine cells. The present study has used an excitotoxic approach employing subcutaneous injections of l-glutamate to ablate these cholinergic amacrine cells on P-7, in order to see whether their elimination alters this targeting of photoreceptor terminals within the IPL. The near-complete elimination of cholinergic amacrine cells at P-15 was confirmed, although the population of retinal ganglion cells was also affected, being depleted by roughly 50%. The rod opsin-immunopositive terminals in such treated ferrets no longer showed a stratified distribution, being found throughout the depth of the IPL, as well as extending into the ganglion cell layer. This effect should not be due to the partial loss of retinal ganglion cells, however, since optic nerve transection at P-2, which eliminates the ganglion cells entirely while leaving the cholinergic amacrine cell population intact, was shown not to affect the stratification pattern of the photoreceptors within the IPL. These results strongly suggest that the targeting of the photoreceptor terminals to discrete strata within the IPL is dependent upon the cholinergic amacrine cell processes.

The present study has examined the emergence of cholinergic stratification within the developing inner plexiform layer (IPL), and the effect of ablating the cholinergic amacrine cells on the formation of other stratifications within the IPL. The population of cholinergic amacrine cells in the ferret's retina was identified as early as the day of birth, but their processes did not form discrete strata until the end of the first postnatal week. As development proceeded over the next five postnatal weeks, so the positioning of the cholinergic strata shifted within the IPL toward the outer border, indicative of the greater ingrowth and elaboration of processes within the innermost parts of the IPL. To examine whether these cholinergic strata play an instructive role upon the development of other stratifications which form within the IPL, one-week-old ferrets were treated with l-glutamate in an attempt to ablate the population of cholinergic amacrine cells. Such treatment was shown to be successful, eliminating all of the cholinergic amacrine cells as well as the alpha retinal ganglion cells in the central retina. The remaining ganglion cell classes as well as a few other retinal cell types were partially reduced, while other cell types were not affected, and neither retinal histology nor areal growth was compromised in these ferrets. Despite this early loss of the cholinergic amacrine cells, which are eliminated within 24 h, other stratifications within the IPL formed normally, as they do following early elimination of the entire ganglion cell population. While these cholinergic amacrine cells are present well before other cell types have differentiated, apparently neither they, nor the ganglion cells, play a role in determining the depth of stratification for other retinal cell types.

Glutamate and γ-aminobutyric acid (GABA) are the dominant amino acids in the retina and brain. The manufacturing and degradation pathways of both of these amino acids are intricately linked with the tricarboxylic acid cycle leading to rapid redistribution of these amino acids after metabolic insult. Postmortem ischemia in mammalian retina predominantly results in a loss of glutamate and GABA from neurons and accumulation of these amino acids within Müller cells. This accumulation of glutamate and GABA in Müller cells may occur as a result of increased release of these neurotransmitters from neurons, and decreased degradation. Quantification of the semisaturation value (half-maximal response) for glutamate and GABA Müller cell loading during postmortem ischemia indicated a shorter semisaturation value for GABA than glutamate. Such changes are consistent with a single aerobically dependent GABA-degradation pathway, and the existence of multiple glutamate-degradation pathways. Comparison with the in vitro ischemic model showed similar qualitative characteristics, but a markedly increased semisaturation time for glutamate and GABA Müller cell loading (a factor of 5–10) in the postmortem ischemia model. We interpret these differences to indicate that the in vitro condition provides a more immediate and/or severe ischemic insult. In the postmortem ischemia model, the delayed glial cell loading implies the availability of internal stores of both glucose and/or oxygen. Increased glial and neuronal immunoreactivity for the amino acids involved in transamination reactions, aspartate, alanine, leucine, and ornithine was observed, indicating a potential shift in the equilibrium of transamination reactions associated with glutamate production. These findings provide evidence that, in the rat retina, there are multiple pathways subserving glutamate production/degradation that include a multitude of transamination reactions. Further evidence is therefore provided to support a role for all four amino acids in glutamate metabolism within a variety of retinal neurons and glia.

The effects of kainate receptor-preferring glutamate ligands were tested on the electroretinogram (ERG) of the Xenopus retina. Kainate, domoic acid, and 5-iodowillardiine (20–100 μM) acted similarly in every respect. They increased peak amplitudes of the ERG a-, b-, and d-waves significantly over controls. The AMPA-specific antagonist, GYKI 53655, prevented a kainate-induced increase in ERG a- and d-waves, but was without effect on an increase in the b-wave. Once the effect of agonist on the b-wave had peaked, the ERG began to subside, leading to its nearly complete disappearance within 20 min. Prior exposure to GYKI followed by a combination of GYKI + agonist did not significantly slow the rate of b-wave disappearance. Our results indicate that (1) AMPA receptors contribute to ERG a- and d-waves. (2) The kainate-evoked increase in ERG a-, b-, and d-waves probably results, in part, from an excitotoxic swelling of inner retinal processes. (3) The inner retina has a population of GYKI-resistant, kainate-sensitive receptors which may contribute to b-wave generation.

The last decade has witnessed a significant turn in our understanding of the mechanisms responsible for the decline of cognitive functions in aged brain. As has been demonstrated by detailed morphological reassessments, the senescence-related changes in cognition cannot be attributed to a simple decrease in the number of neurons. It is becoming clearer that a major cause of age-induced deterioration of brain capability involves much subtler changes at the level of synapses. These changes are either morphological, i.e. reduction in the number of effective synapses and/or functional alterations, i.e. changes in the efficacy of remaining synapses. Important questions are now raised regarding the mechanisms which mediate these synaptic changes. Clearly, an important candidate is calcium, the cytotoxic role of which is already firmly established. The wealth of evidence collected so far regarding the changes of Ca2+ homeostasis in aged neurons shows that the overall duration of cytoplasmic Ca2+ signals becomes longer. This is the most consistent result, demonstrated on different preparations and using different techniques. What is not yet clear is the underlying mechanism, as this result could be explained either through an increased Ca2+ influx or because of a deficit in the Ca2+ buffering/clearance systems. It is conceivable that these prolonged Ca2+ signals may exert a local excitotoxic effect, removing preferentially the most active synapses. Uncovering of the role of Ca2+ in the synaptic function of the aged brain presents an exciting challenge for all those involved in the neurobiology of the senescent CNS.

The high-affinity uptake of glutamate by glial cells and neurons of the central nervous system, including the retina, serves to inactivate synaptically released glutamate and maintains glutamate at low concentrations in the extracellular space. This uptake prevents accumulation of glutamate extracellularly and thus minimizes the possibility of glutamate neurotoxicity secondary to ischemic insult. One mechanism whereby glutamate neurotoxicity may occur in ischemic/hypoxic insult is through increased extracellular K+ reversing the electrogenic glutamate uptake into retinal glial (Müller) cells. We investigated glial uptake of the amino acids glutamate, GABA, and D-aspartate in the intact isolated rat retina under high extracellular K+ conditions and under conditions simulating ischemia. Immunocytochemical findings showed that uptake of glutamate and GABA by Müller cells in the intact isolated rat retina continues under conditions simulating ischemia and high extracellular K+ conditions, and uptake of D-aspartate also continues under high K+ conditions. However, under high K+ conditions, the glutamate uptake system saturates at a lower concentration of exogenous glutamate than in the normal K+ condition. These findings provide evidence that disruption of glutamate uptake by Müller cells is likely to be a significant contributing factor to excess glutamate accumulation in the extracellular space which can lead to neurotoxicity.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate glutamatergic neurotransmission, and when pathologically overstimulated induce excitotoxic neuronal death. Of the two families of iGluRs, the non-NMDA receptors have received less experimental attention than the NMDA receptors as mediators of neuronal death in in vitro systems. We have demonstrated that non-NMDA receptor activation is highly lethal for neurons of the chick embryo retina, and further characterize this phenomenon here. Treatment of isolated retinas with any of the non-NMDA receptor agonists glutamate, AMPA, or KA, in the presence of the NMDA receptor antagonist MK-801, led to pathomorphology and cell death. KA was the most effective toxin. All of KA-induced toxicity could be blocked by selective AMPA receptor blockers. The toxicity of both AMPA and glutamate could be greatly increased using cyclothiazide, which blocks AMPA receptor desensitization. These results indicate that KA is the most powerful toxin because it is a non-desensitizing agonist at the AMPA receptors. Glutamate exhibited a paradoxical ability to prevent KA-induced toxicity as measured by a biochemical assay of cell death. Also, histological studies indicated that glutamate selectively blocked KA-induced pathomorphological changes in bipolar cells. This protective effect of glutamate was not mimicked by AMPA, NMDA, or any of several metabotropic receptor agonists, indicating that it may be mediated by a receptor of undescribed pharmacology.