Recent studies have demonstrated neural overlap between resting state activity and self-referential processing. This “rest-self” overlap occurs especially in anterior cortical midline structures like the perigenual anterior cingulate cortex (PACC). However, the exact neurotemporal and biochemical mechanisms remain to be identified. Therefore, we conducted a combined electroencephalography (EEG)-magnetic resonance spectroscopy (MRS) study. EEG focused on pre-stimulus (e.g., prior to stimulus presentation or perception) power changes to assess the degree to which those changes can predict subjects’ perception (and judgment) of subsequent (...) stimuli as high or low self-related. MRS measured resting state concentration of glutamate, focusing on PACC. High pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power significantly correlated with both perception of stimuli judged to be highly self-related and with resting state glutamate concentrations in the PACC. In sum, our results show (i) pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power and resting state glutamate concentration to mediate rest-self overlap that (ii) dispose or incline subjects to assign high degrees of self-relatedness to perceptual stimuli. (shrink)

Genetic abnormalities of three factors related to the photoreceptor mechanism have been reported in both animal models and humans. Apoptotic mechanism has also been suggested as a final common pathway of photoreceptor cell death. Our findings of increased level of glutamate in photoreceptor cells in rds mice suggest that amino acid might mediate between these two pathological mechanisms.

IntroductionSymptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of “negative formal thought disorder”.MethodsAtlas-based cortical thickness values of 66 (...) patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex ] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion.ResultsTwo neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units and lower repeats of content words, despite being equally fluent.ConclusionWe characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry and language behavior. This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia. (shrink)

IntroductionCognitive impairment is a highly prevalent non-motor feature of Parkinson’s disease. A better understanding of the underlying pathophysiology may help in identifying therapeutic targets to prevent or treat dementia. This study sought to identify metabolic alterations in the prefrontal cortex, a key region for cognitive functioning that has been implicated in cognitive dysfunction in PD.MethodsProton Magnetic Resonance Spectroscopy was used to investigate metabolic changes in the PFC of a cohort of cognitively normal individuals without PD, as well as PD participants (...) with either normal cognition, mild cognitive impairment, or dementia. Ratios to Creatine resonance were obtained for glutamate, glutamine and glutamate combined, N-acetylaspartate, myoinositol, and total choline, and correlated with cognitive scores across multiple domains administered to the PD participants only.ResultsWhen individuals retain cognitive capabilities, the presence of Parkinson’s disease does not create metabolic disturbances in the PFC. However, when cognitive symptoms are present, PFC Glu/Cre ratios decrease with significant differences between the PD-NC and PPD groups. In addition, Glu/Cre ratios and memory scores were marginally associated, but not after Bonferroni correction.ConclusionThese preliminary findings indicate that fluctuations in prefrontal glutamate may constitute a biomarker for the progression of cognitive impairments in PD. We caution for larger MRS investigations of carefully defined PD groups. (shrink)

Organogenesis and metamorphosis require the intricate orchestration of multiple types of cellular interactions and signaling pathways. Glutamate (Glu) is an excitatory extracellular signaling molecule in the nervous system, while Ca2+ is a major intracellular signaling molecule. The first Glu receptors to be cloned are Ca2+‐permeable receptors in mammalian brains. Although recent studies have focused on Glu signaling in synaptic mechanisms of the mammalian central nervous system, it is unclear how this signaling functions in development. Our recent article demonstrated that (...) Ca2+‐permeable AMPA‐type Glu receptors (GluAs) are essential for formation of a photosensitive organ, development of some neurons, and metamorphosis, including tail absorption and body axis rotation, in ascidian embryos. Based on findings in these embryos and mammalian brains, we formed several hypotheses regarding the evolution of GluAs, the non‐synaptic function of Glu, the origin of GluA‐positive neurons, and the neuronal network that controls metamorphosis in ascidians. (shrink)

This hypothesis proposes that increased extracellular glutamate in Amyotrophic Lateral Sclerosis (ALS) and cerebral ischemia, currently viewed as a trigger for excitotoxicity, is actually beneficial as it stimulates the utilization of glutamate as metabolic fuel. Renewed appreciation of glutamate oxidation by ischemic neurons has raised questions regarding the role of extracellular glutamate in ischemia. Is it detrimental, as suggested by excitotoxicity in early in vitro studies, or beneficial, as suggested by its oxidation in later in vivo (...) studies? The answer may depend on the activity of N‐methyl‐D‐aspartate (NMDA) glutamate receptors. Early in vitro procedures co‐activated NMDA receptors (NMDARs) containing 2A (GluN2A) and 2B (GluN2B) subunits, an event now believed to trigger excitotoxicity; however, during in vivo ischemia D‐serine and zinc molecules are released and these ensure only GluN2B receptors are stimulated. This not only prevents excitotoxicity but also initiates signaling cascades that allow ischemic neurons to import and oxidize glutamate. (shrink)

It was initially believed that G‐protein‐coupled receptors, such as metabotropic glutamate receptors, could simply be described as individual proteins that are associated with intracellular signal cascades via G‐proteins. This view is no longer tenable. Today we know that metabotropic glutamate receptors (mGluRs) can dimerize and bind to a variety of proteins in addition to trimeric G‐proteins. These newly identified protein interactions led to the discovery of new regulatory mechanisms that are independent of and sometimes synergistic with the classical (...) G‐protein‐coupled second messenger pathways. Notably, several of these mechanisms connect mGluR‐mediated signaling to other receptor classes, thereby creating a network of different receptor types and associated signal cascades. The intracellular C‐termini of mGluRs play a key role in the regulation of these networks, and various new protein interactions of these domains were described recently. Because mGluRs are involved in a variety of physiological and pathophysiological processes, some of the proteins interacting with this receptor class have potential as valuable pharmaceutical targets. This review will give a comprehensive overview of proteins interacting with mGluR C‐termini, highlight new evolving regulatory mechanisms for glutamatergic signal transduction and discuss possibilities for future drug development. BioEssays 29: 60–73, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L‐ (...) class='Hi'>glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy. (shrink)

The concept of locally specialized functions dominates research on higher brain function and its disorders. Locally specialized functions must be complemented by processes that coordinate those functions, however, and impairment of coordinating processes may be central to some psychotic conditions. Evidence for processes that coordinate activity is provided by neurobiological and psychological studies of contextual disambiguation and dynamic grouping. Mechanisms by which this important class of cognitive functions could be achieved include those long-range connections within and between cortical regions that (...) activate synaptic channels via NMDA-receptors, and which control gain through their voltage-dependent mode of operation. An impairment of these mechanisms is central to PCP-psychosis, and the cognitive capabilities that they could provide are impaired in some forms of schizophrenia. We conclude that impaired cognitive coordination due to reduced ion flow through NMDA-channels is involved in schizophrenia, and we suggest that it may also be involved in other disorders. This perspective suggests several ways in which further research could enhance our understanding of cognitive coordination, its neural basis, and its relevance to psychopathology. Key Words: attention; cerebral cortex; cognitive coordination; cognitive neuropsychiatry; cognitive neuropsychology; context disorganization; Gamma rhythms; Gestalt theory; glutamate; grouping; memory; NMDA-receptors; PCP-psychosis; perceptual organization; schizophrenia. (shrink)

For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several such mutations have already (...) been identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders. (shrink)

Glutamate is the major excitatory neurotransmitter in the mammalian brain, with receptors on every neuron in the central nervous system; it has major roles in fast synaptic transmission and in the establishment of certain forms of memory. More than 20 years ago Olney and his colleagues(1) described the [Excitotoxic Hypothesis] which postulates that, in addition to its normal function in the healthy brain, glutamate can kill neurons by prolonged, receptorsmediated depolarization resulting in irreversible disturbances in ion homeostasis. Therefore, (...) glutamate is a two‐edged sword; in certain undefined, adverse conditions it undergoes a transition from neurotransmitter to neurotoxin. Its toxicity has been implicated in the death of neurons in ischemia, epilepsy, and the neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's diseases(2–5). Recent advances in the molecular cloning of the genes for the glutamate family of receptors has revealed a plethora of receptor subtypes and an unexpected level of complexity in the mechanisms of receptor expression and function. (shrink)

MutL family proteins contain an N‐terminal ATPase domain (NTD), an unstructured interdomain linker, and a C‐terminal domain (CTD), which mediates constitutive dimerization between subunits and often contains an endonuclease active site. Most MutL homologs direct strand‐specific DNA mismatch repair by cleaving the error‐containing daughter DNA strand. The strand cleavage reaction is poorly understood; however, the structure of the endonuclease active site is consistent with a two‐ or three‐metal ion cleavage mechanism. A motif required for this endonuclease activity is present in (...) the unstructured linker of Mlh1 and is conserved in all eukaryotic Mlh1 proteins, except those from metamonads, which also lack the almost absolutely conserved Mlh1 C‐terminal phenylalanine‐glutamate‐arginine‐cysteine (FERC) sequence. We hypothesize that the cysteine in the FERC sequence is autoinhibitory, as it sequesters the active site. We further hypothesize that the evolutionary co‐occurrence of the conserved linker motif with the FERC sequence indicates a functional interaction, possibly by linker motif‐mediated displacement of the inhibitory cysteine. This role is consistent with available data for interactions between the linker motif with DNA and the CTDs in the vicinity of the active site. (shrink)

Because little is known about the human trait of affiliation, we provide a novel neurobehavioral model of affiliative bonding. Discussion is organized around processes of reward and memory formation that occur during approach and consummatory phases of affiliation. Appetitive and consummatory reward processes are mediated independently by the activity of the ventral tegmental area (VTA) dopamine (DA)–nucleus accumbens shell (NAS) pathway and the central corticolimbic projections of the u-opiate system of the medial basal arcuate nucleus, respectively, although these two projection (...) systems functionally interact across time. We next explicate the manner in which DA and glutamate interact in both the VTA and NAS to form incentive-encoded contextual memory ensembles that are predictive of reward derived from affiliative objects. Affiliative stimuli, in particular, are incorporated within contextual ensembles predictive of affiliative reward via: (a) the binding of affiliative stimuli in the rostral circuit of the medial extended amygdala and subsequent transmission to the NAS shell; (b) affiliative stimulus-induced opiate potentiation of DA processes in the VTA and NAS; and (c) permissive or facilitatory effects of gonadal steroids, oxytocin (in interaction with DA), and vasopressin on (i) sensory, perceptual, and attentional processing of affiliative stimuli and (ii) formation of social memories. Among these various processes, we propose that the capacity to experience affiliative reward via opiate functioning has a disproportionate weight in determining individual differences in affiliation. We delineate sources of these individual differences, and provide the first human data that support an association between opiate functioning and variation in trait affiliation. Key Words: affiliation corticolimbic-striatal networks; appetitive and consummatory reward; dopamine; oxytocin; personality; social bonds; social memory; u-opiates. (shrink)

Studies have shown that both serotonin and glutamate receptor systems play a crucial role in the mechanisms underlying drug-induced synesthesia. The specific nature of these mechanisms, however, continues to remain elusive. Here we propose two distinct hypotheses for how synesthesia triggered by hallucinogens in the serotonin-agonist family may occur. One hypothesis is that the drug-induced destabilization of thalamic projections via GABAergic neuronal circuits from sensory areas leads to a disruption of low-level, spontaneous integration of multisensory stimuli. This sort of (...) integration regularly occurs when spatial and temporal attributes match. Destabilization of feedback loops, however, can result in incongruent experiences or binding of random thalamus activation with sensory input in a particular sensory modality. The second hypothesis builds on embodied cognition, cases in which visual images of external stimuli activate task-related neural regions. On this proposal, binding processes that do not normally generate awareness become accessible to consciousness as a result of decreased attentional discrimination among incoming stimuli. (shrink)

Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Inattentiveness, overactivity, and impulsiveness are presently regarded as the main clinical symptoms. The dynamic developmental behavioral theory is based on the hypothesis that altered dopaminergic function plays a pivotal role by failing to modulate nondopaminergic (primarily glutamate and GABA) signal transmission appropriately. A hypofunctioning mesolimbic dopamine branch produces altered reinforcement of behavior and deficient extinction of previously reinforced behavior. This gives rise to (...) delay aversion, development of hyperactivity in novel situations, impulsiveness, deficient sustained attention, increased behavioral variability, and failure to “inhibit” responses (“disinhibition”). A hypofunctioning mesocortical dopamine branch will cause attention response deficiencies (deficient orienting responses, impaired saccadic eye movements, and poorer attention responses toward a target) and poor behavioral planning (poor executive functions). A hypofunctioning nigrostriatal dopamine branch will cause impaired modulation of motor functions and deficient nondeclarative habit learning and memory. These impairments will give rise to apparent developmental delay, clumsiness, neurological “soft signs,” and a “failure to inhibit” responses when quick reactions are required. Hypofunctioning dopamine branches represent the main individual predispositions in the present theory. The theory predicts that behavior and symptoms in ADHD result from the interplay between individual predispositions and the surroundings. The exact ADHD symptoms at a particular time in life will vary and be influenced by factors having positive or negative effects on symptom development. Altered or deficient learning and motor functions will produce special needs for optimal parenting and societal styles. Medication will to some degree normalize the underlying dopamine dysfunction and reduce the special needs of these children. The theory describes how individual predispositions interact with these conditions to produce behavioral, emotional, and cognitive effects that can turn into relatively stable behavioral patterns. Key Words: catecholamine; clumsiness; dopamine; hyperkinesis; hyperkinetic disorder; impulsivity; monoamine; neuromodulator; overactivity; pollutants; reinforcement; reward; verbally governed behavior; soft signs; variability. (shrink)

Disorders of consciousness and the self are at the forefront of schizophrenia symptomatology. Patients are impaired in feeling themselves as the authors of their thoughts and actions. In addition, their flow of consciousness is disrupted, and thought fragmentation has been suggested to be involved in the patients’ difficulties in feeling as being one unique, unchanging self across time. Both impairments are related to self disorders, and both have been investigated at the experimental level. Here we review evidence that both mechanisms (...) of motor control and the temporal structure of signal processing are impaired in schizophrenia patients. Based on this review, we propose that the sequencing of action and perception plays a key role in the patients’ impairments. Furthermore, the millisecond time scale of the disorders, as well as the impaired sequencing, highlights the cooperation between brain networks including the cerebellum, as proposed by Andreasen (1999). We examine this possibility in the light of recent knowledge on the anatomical and physiological properties of the cerebellum, its role in timing, and its involvement in known physiological impairments in patients with schizophrenia, e.g., resting states and brain dynamics. A disruption in communication between networks involving the cerebellum, related to known impairments in dopamine, glutamate and GABA transmission, may help to better explain why patients experience reduced attunement with the external world and possibly with themselves. (shrink)

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and (...) right cerebellum and structural changes in various brain regions of patients with gluten ataxia and compared it with healthy controls. Volumetric 3-D T1 and T1-weighted magnetic resonance imaging in the three planes of the whole brain and single-voxel 1H- magnetic resonance spectroscopy of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of ; reduction in the volumes of cerebellum lobe and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients. (shrink)

Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually (...) impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsive behavior. The ability of addictive drugs to co‐opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction. (shrink)

Backgrounds: Transcranial direct current stimulation is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, e.g., mood disorders and schizophrenia. Therapeutic effects of tDCS are suggested to be produced by bi-directional changes in cortical activities, i.e., increased/decreased cortical excitability via anodal/cathodal stimulation. Although tDCS provides a promising approach for the treatment of psychiatric disorders, its neurobiological mechanisms remain to be explored.Objectives: To review recent findings from neurophysiological, chemical, and brain-network studies, and consider how tDCS ameliorates psychiatric conditions.Findings: (...) Enhancement of excitatory synaptic transmissions through anodal tDCS stimulation is likely to facilitate glutamate transmission and suppress gamma-aminobutyric acid transmission in the cortex. On the other hand, it positively or negatively modulates the activities of dopamine, serotonin, and acetylcholine transmissions in the central nervous system. These neural events by tDCS may change the balance between excitatory and inhibitory inputs. Specifically, multi-session tDCS is thought to promote/regulate information processing efficiency in the cerebral cortical circuit, which induces long-term potentiation by synthesizing various proteins.Conclusions: This review will help understand putative mechanisms underlying the clinical benefits of tDCS from the perspective of neurotransmitters, network dynamics, intracellular events, and related modalities of the brain function. (shrink)

Activating the ERK pathway (extracellular signal‐regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs (...) a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK‐dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down‐regulating ERK‐dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, arachidonic (...) acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

A biological explanation for the dependence of genome-wide mutation-rate variation on local base context is now becoming clearer. The proportions of G + C relative to A + T—expressed as GC%—is a species-specific DNA character. The frequencies of these single bases correlate with frequencies of corresponding oligonucleotides that are more-sensitive indicators of species specificity. Thus, when k = 3 there are 64 possible trinucleotide sequences and a GC%-rich species has a high frequency of GC-rich 3-mers. Closely related species have similar (...) k-mer patterns. For distantly related species, even if happening to have the same GC% values, k-mer patterns are widely discordant. Conventionally, a base substitution mutation is viewed as a chemical 1-mer phenomenon. However, the selective difference by which the corresponding mutation is scored usually relates to context. Thus, an A to U codon mutation in sickle cell anemia, rather than attracting an anticodon in a structural loop of glutamate tRNA, pairs with the more complementary anticodon loop of valine tRNA. Likewise, a recent statistical analysis of genome-wide mutation-rate variation supports the view that a failure of discordant DNA loops to pair at meiosis can initiate and/or sustain the speciation process. Such disharmony among base patterns may have unknowingly been hinted at by geneticist William Bateson who invoked a music metaphor when considering speciation mechanisms. (shrink)

Vincent proposes that the extracellular cGMP found in cerebellum after glutamate receptor activation is released mainly from Purkinje cells because in these neurons the presence of guanylate cyclase has been shown using monoclonal antibodies. It is uncertain, however, whether Purkinje cells are the only source of extracellular cGMP in the cerebellum. This commentary examines the possibility that glial and cerebellar granule cells may also participate in cGMP synthesis and release, Moreover, the hypothesis of transcellular metabolism of citrulline and arginine (...) is discussed. [VINCENT]. (shrink)

Recent studies from several different laboratories have provided further insight into structure-function relationships of cyclic nucleotide-gated channel and in particular the cCMPgated channel of rod photoreceptors. Site-directed mutagenesis and rod-olfactory chimeria constructs have defined important amino acids and peptide segments of the channel that are important in ion blockage, ligand specificity, and gating properties. Molecular cloning studies have indicated that cyclic nucleotide-gated channels consist of two subunits that are required to reproduce the properties of the native channels. Biochemical analysis of (...) the cGMP-gated channel of rodcells have indicated that the 240 kDa protein that co-purifies with the 63 kDa channel subunit contains both the previously cloned second subunit of the channel and a glutamic acid-rich protein. The regulatory properties of the cGMP-gated channel from rod cells has also been studied in more detail. Studies indicate that the beta subunit of the cGMP-gated channel of rod cells contains the binding site for calmodulin. Interaction of calmodulin with the channel alters the apparent affinity of the channel for cGMP in all in vitro systems that have been studied. The significance of these recent studies are discussed in relation to the commentaries on the target article. (shrink)

Methionine aminopeptidases with a universal specificity have been revealed from the sequences of the amino‐terminal region of mutant forms of yeast iso‐1‐cytochrome c and from a systematic examination of the literature for amino‐terminal sequences formed at initiation sites. The aminopeptidase removes amino‐terminal residues of methionine when they precede certain amino acids, with a specificity that appears to be determined mainly by the residue adjacent to the methionine residue at the amino terminus. The result with the mutationally altered iso‐1‐cytochromes c and (...) the results from published sequences of other proteins from a wide range of prokaryotes and eukaryotes suggest that the aminopeptidase usually cleaves amino‐terminal methionine when it precedes residues of alanine, cysteine, glycine, proline, serine, threonine and valine but not when it precedes residues of arginine, asparagine, aspartic acid, glutamine, glutamic acid, isoleucine, leucine, lysine or methionine. We suggest that the specificity is almost always determined simply by the size of the side chain of the penultimate residue; methionine is usually cleaved from residues with a side chain having a radius of gyration of 1·29 Å or less, but is not cleaved from residues with larger side chains. (shrink)

Sickle cell anemia is a disease characterized by abnormal hemoglobin structure. There is a mutation in the beta-globin gene that changes the sixth amino acid from glutamic acid to valine causing the mutated hemoglobin to polymerize reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen and distort the red blood cell membrane. This leads to episodes of microvascular vasoocclusion and premature RBC destruction leading to hemolytic anemia. For reasons that are unclear, some children develop a large (...) artery vasculopathy involving the intracranial arteries supplying the brain.The risk of stroke for a child with SCD is many times greater than that of a healthy child without SCD or heart disease. There is a technique that allows the identification of the children with SCD who have high risk even within this relatively high-risk group. And there is a highly effective preventive treatment. (shrink)

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (AD). (...) We propose that an increase in tau acetylated on these lysines blocks the expression of long‐term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity‐dependent recruitment of postsynaptic AMPA‐type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory‐associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. (shrink)

Recent studies have provided evidence of associations between neurochemistry and reading (dis)ability (Pugh et al., 2014). Based on a long history of studies indicating that fluent reading entails the automatic convergence of the written and spoken forms of language and our recently proposed Neural Noise Hypothesis (Hancock et al., 2017), we hypothesized that individual differences in cross-modal integration would mediate, at least partially, the relationship between neurochemical concentrations and reading. Cross-modal integration was measured in 231 children using a two-alternative forced (...) choice cross-modal matching task with three language conditions (letters, words, and pseudowords) and two levels of difficulty within each language condition. Neurometabolite concentrations of Choline (Cho), Glutamate (Glu), gamma-Aminobutyric (GABA), and N- acetyl-aspartate (NAA) were then measured in a subset of this sample (n = 70) with Magnetic Resonance Spectroscopy (MRS). A structural equation mediation model revealed that the effect of cross-modal word matching mediated the relationship between increased Glu (which has been proposed to be an index of neural noise) and poorer reading ability. In addition, the effect of cross-modal word matching fully mediated a relationship between increased Cho and poorer reading ability. Multilevel mixed effects models confirmed that lower Cho predicted faster cross-modal matching reaction time, specifically in the hard word condition. These Cho... (shrink)

White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy in the prefrontal white matter at the beginning and end of season in contact and non-contact varsity athletes. Sedentary women were scanned once, at a time equivalent to (...) the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline. (shrink)

Elevations in brain stimulation reward (BSR) thresholds have been observed in rats undergoing nicotine withdrawal and have been proposed as a sensitive measure of the negative affective state associated with nicotine withdrawal. mGluR are presynaptic autoreceptors that decrease glutamate release when stimulated. The aim of this study was to examine the role of glutamate neurotransmission in nicotine dependence. The mGluR agonist LY314582 (2.5–7.5 mg/kg) precipitated nicotine withdrawal as measured by elevations in BSR thresholds in nicotine-treated rats but not (...) in controls. It was hypothesized that LY314582 precipitated nicotine withdrawal by decreasing glutamatergic tone at postsynaptic glutamate receptors. Therefore, the effects of MPEP (0.5–2 mg/kg), an mGluR antagonist, and MK-801 (0.01–1 mg/kg), an NMDA receptor antagonist, were examined. MPEP elevated BSR thresholds by an equal magnitude in control and nicotine-treated rats. At low doses, MK-801 (0.01–0.2 mg/kg) lowered BSR thresholds to a similar extent in control and nicotine-treated rats. At higher doses, MK-801 (0.25–1 mg/kg) disrupted performance in nicotine-treated and control rats. These data indicate that mGluR and NMDA receptors regulate BSR in opposite directions in non-dependent animals, and chronic nicotine treatment does not alter these effects. Most importantly, the data demonstrate that the mGluR is involved in nicotine dependence, but mGluR and NMDA receptors do not mediate mGluR actions in nicotine dependence. (shrink)

Current research on the neural basis of consciousness is based mainly on neuroimaging, physiology and psychophysics. This target article reviews what is known about biochemical factors that may contribute to the development of consciousness, based on loss of consciousness (i.e., coma). There are two theories of the biochemical mode of action of general anaesthetics. One is that anaesthesia is a direct (i.e., not receptor-mediated) effect of the anaesthetic on cellular neurophysiological function; the other is that some alteration of receptor function (...) occurs. General anaesthetics are mainly GABA agonists but some (such as ketamine) are glutamate antagonists. They also affect other systems, particularly cholinergic ones. There are various comas of metabolic origin. For example, a combination of small doses of the iron chelators desferrioxamine and prochlorperazine induce a profound and long lasting coma in humans. The mechanisms that might mediate this include redox mechanisms at the glutamate synapse, post-synaptic endocytosis of dopamine and iron, and intracellular iron-dopamine complexes, which are powerful dismuters of the superoxide anion. New findings in cell biology relating to endocytosis and recycling of receptors are discussed in a wider context. These biochemical events may induce coma by two mechanisms: (i) Consciousness may depend on widespread cortical (or cortico-thalamic) activation. (ii) Whereas these biochemical changes are widespread, only the changes in a subset of consciousness' neurons may count. An experimental program to distinguish between these two alternatives is proposed. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of (...) autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

Phillips & Silverstein offer an exciting synthesis of ongoing efforts to link the clinical and cognitive manifestations of schizophrenia with cellular accounts of its pathophysiology. We applaud their efforts but wonder whether the highly inclusive notion of “context” adequately captures some important details regarding schizophrenia and NMDA/glutamate function that are suggested by work on language processing and cognitive electrophysiology.

Oligodendrocytes are known to express Ca2+-permeable glutamate receptors and to have low resistance to oxidative stress, two factors that make them potentially susceptible to injury. Oligodendrocyte injury is intrinsic to the loss of function experienced in conditions ranging from cerebral palsy to spinal cord injury, focal ischaemia and multiple sclerosis. NMDA receptors, a subtype of glutamate receptors, are vital to the remodeling of synaptic connections during postnatal development and associative learning abilities in adults and possibly in improvements in (...) oligodendrocyte function. Previous studies had failed to detect NMDA receptor mRNA or current in oligodendrocytes but three new papers1-3 demonstrate NMDA receptor expression in oligodendrocytes and discuss its implications for ischaemia therapy. BioEssays 28: 460–464, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including (...) production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

Pains that persist long after damaged tissue hasrecovered remain a perplexing phenomenon. Theseso-called chronic pains serve no useful function foran organism and, given its disabling effects, mighteven be considered maladaptive. However, a remarkablesimilarity exists between the neural bases thatunderlie the hallmark symptoms of chronic pain andthose that subserve learning and memory. Bothphenomena, wind-up in the pain literature andlong-term potentiation (LTP) in the learning andmemory literature, are forms of neuroplasticity inwhich increased neural activity leads to a longlasting increase in the excitability (...) of neuronsthrough structural modifications at pre- andpost-synaptic sites. Moreover, the synapticmodifications of wind-up and LTP share a commonmechanism: a glutamate N -methyl-D-aspartate(NMDA) receptor interaction that initiates a calciummediated biochemical cascade that ultimately enhancessignal processing at the -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor. This paper arguesthat chronic pain, which has no adaptive value, canbe accounted for in terms of the highly adaptivephenomenon of activity-dependent neural plasticity;hence, some cases of chronic pain can beconceptualized as a memory trace in spinal neurons. (shrink)

Nitric oxide (NO) is involved in synaptic long-term potentiation (LTP) by multiple signaling pathways. Here, we show that LTP of synaptic transmission can be explained as a feature of signal transduction—bistable behavior in a chain of biochemical reactions with positive feedback, formed by diffusion of NO to the presynaptic site and facilitating the release of glutamate (Glu). The dynamics of Glu, calcium (Ca2+) and NO is described by a system of nonlinear reaction–diffusion equations with modified Michaelis–Menten (MM) kinetics. Numerical (...) investigation reveals that the chain of biochemical reactions analyzed can exhibit a bistable behavior under physiological conditions when production of Glu is described by MM kinetics and decay of NO is modeled by means of two enzymatic pathways with different kinetic properties. Our finding extends understanding of the role of NO in LTP: a short high-intensity stimulus is “memorized” as a long-lasting elevation of NO concentration. The conclusions obtained by analysis of the chain of biochemical reactions describing LTP can be generalized to other chains of interactions or for creating the logical elements for biological computers. (shrink)

Stiff Person Syndrome is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase, the key enzyme in γ -aminobutyric acid synthesis. In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [ 11 C]flumazenil positron emission tomography in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction of (...) cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS. (shrink)

Defects in man in four steps of 4‐aminobutyric acid (GABA) metabolism may interefere with the function of this major inhibitory neurotransmitter. Glutamic acid decarboxylase, 4‐aminobutyric acid aminotransferase, succinic semialdehyde dehydrogenase, and homocarnosinase are closely identified with the brain, but two of these enzymes are expressed in cultured peripheral cells, which may permit novel approaches to the study of the metabolism and regulation of GABA.

The claim that the disorganized subtype of schizophrenia results from glutamate hypofunction is enhanced by consideration of current subtypology of schizophrenia, symptom definition, interdependence of neurotransmitters, and the nature of the data needed to support the hypothesis. Careful specification clarifies the clinical reality of disorganization as a feature of schizophrenia and increases the utility of the subtype.