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Glutamate hypofunction hypothesis of schizophrenia

NMDAr hypofunction and gamma oscillations may be related to some but not all cognitive symptoms relevant to schizophrenia.

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Schizophrenia, NMDA Hypofunction; ..

Determining the causes and consequences of altered GABAergic transmission in the cortical and hippocampal networks of schizophrenics requires knowledge of which subpopulations of GABAergic neurons are affected. Interneuron alterations in schizophrenia, especially parvalbumin and somatostatin containing interneurons are likely to have significant effects on the network oscillatory activity and therefore on cognitive processes depending on the integration of neuronal signals in the brain (Gonzalez-Burgos et al., ; Morris et al., ). However, extensive functional studies of specific interneuron populations at the cellular and systems level in different brain regions were hampered by the difficulty of identifying these neurons during experiments. Using enhanced green fluorescence protein expressing mice under the control of different (e.g. parvalbumin or somatostatin) gene promoters has significantly facilitated the identification of these types of cells in the acute slice preparation (Meyer et al., ; Oliva et al., ). In addition, given the relative ease with which oscillatory activity can be induced in slice preparations, it follows that these network activities and the participating interneurons can be investigated in vitro in NMDA-hypofunction models (see e.g. Behrens et al., ; Braun et al., ; Cunningham et al., ), thereby increasing our understanding of complex electrophysiological behaviours in the NMDA-hypofunction model of schizophrenia.

evidence in support of the N-methyl-d-aspartate receptor hypofunction hypothesis of schizophrenia

We studied the effect of localised NMDAr hypofunction on the generation of neural oscillations in local and distant regions, as well as behavioural psychosis-related endophenotypes of schizophrenia.

the “NMDA receptor hypofunction hypothesis ..

The NMDAr hypofunction hypothesis of schizophrenia suggests that aberrant signalling through these receptors may underlie symptoms of the disorder.

The NMDA-hypofunction theory can also account for the developmental vulnerability associated with schizophrenia, as well as for its typical age of onset in early adulthood (Thompson et al., ). Thus it has been shown, that during the early developmental stage of synaptogenesis, neurons carrying NMDA receptors are extremely sensitive towards the level of glutamatergic activation they receive, reacting with excitotoxic neurodegeneration towards excessive levels (Ikonomidou et al., ) and with apoptosis towards deficient glutamate stimulation (Ikonomidou et al., ). Therefore an imbalance in glutamate concentrations during this stage, which could be triggered by a simple mechanism such as in utero compression of the umbilical cord, will lead to a selective loss of NMDA-bearing neurons, resulting in a structurally implemented NMDA-hypofunction state (Olney et al., ). This vulnerability is assumed to come into play only in early adulthood, when further developmental processes, such as synaptic pruning, render the brain susceptible to these disease factors (Granger, ). It has been shown that the systemic application of phencyclidines during development can lead to neurodegenerative patterns in corticolimbic regions (Corso et al., ; Ellison, ; Ellison and Switzer, ; Wozniak et al., ), which resemble the structural changes associated with schizophrenia (Heckers et al., ; Konradi and Heckers, ).

The cortical GABAergic interneurons, which are responsible for recurrent inhibition to the pyramidal neurons, were critical for NMDAR hypofunction model as supported by several lines of evidence. Since the first postmortem studies of schizophrenia, GABAergic deficits in cortex and limbic system were reported although whether this was an artifact of the agonal events such as a slow death was a concern. Immunocytochemical studies revealed these recurrent inhibitory neurons represented a subset that expressed parvalbumin (PV) and appeared to be selectively vulnerable in schizophrenia through reduced number or expression of PV, which proved to be robust in quantitative measurements of gene expression. Treatment of mice with ketamine reduces the levels of PV and GAD67 through generation of superoxides and diminishes inhibitory postsynaptic currents on the pyramidal neurons.

NMDA receptor hypofunction model of schizophrenia …

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The implication of the N-methyl-D-aspartate receptor (NMDAR) in the pathophysiology of schizophrenia is a rather recent development with the first associations appearing in print in the 1980s. According to ISI Thomson, there have been over 2000 articles published on the subject since then. This review of the hypothesized role of NMDAR in schizophrenia will focus on articles appearing prior to 2002 (ie, greater than one decade ago) unless they validate or build upon prior findings. More recent articles could be viewed as part of the current research efforts. Decisions about importance and timeliness are based upon the citation record of the articles.

Although glutamate was first hypothesized to be involved in the pathophysiology of schizophrenia in the 1980s, it was the demonstration that N-methyl-D-aspartate (NMDA) receptor antagonists, the dissociative anesthetics, could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects that placed the “NMDA receptor hypofunction hypothesis” on firm footing. Additional support came from the demonstration that a variety of agents that enhanced NMDA receptor function at the glycine modulatory site significantly reduced negative symptoms and variably improved cognition in patients with schizophrenia receiving antipsychotic drugs. Finally, persistent blockade of NMDA receptors recreates in experimental animals the critical pathologic features of schizophrenia including downregulation of parvalbumin-positive cortical GABAergic neurons, pyramidal neuron dendritic dysgenesis, and reduced spine density.

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    NMDA receptors, cognition and schizophrenia – Testing the validity of the NMDA receptor hypofunction hypothesis

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NMDA receptor antagonist - Wikipedia

The use of brain imaging technology to investigate the effects of PCP provides clues to the acute and chronic regional effects of the drug on brain metabolism. Data from receptor binding studies in animals show that limbic regions (especially the hippocampus) contain high concentrations of NMDA receptors (,). Although it may be supposed that PCP would reduce brain metabolism (especially in frontal brain regions to mimic the hypofrontality seen in schizophrenics) [,], studies in animals administered PCP and PCP-like compounds show that PCP increased regional glucose metabolism, specifically in hippocampal regions (,,,). Ketamine, a PCP-like compound, was similarly shown in five of six studies to increase glucose metabolism in hippocampal regions in animals (,,,,). However, schizophrenia is a chronic illness associated with hypothesized reductions in glutamate activity and hypofrontality (). A chronic PCP study by Gao et al. () in rats showed that glucose metabolism was decreased in limbic regions. Lahti et al. () administered ketamine (0.3 mg/kg, i.v.) to a group of schizophrenics stabilized on haloperidol and measured metabolic activity with HO and PET. In these patients, ketamine increased cerebral blood flow in the anterior cingulate cortex and in an area which extended inferiorly to the medial wall of the prefrontal cortex. In contrast, blood flow to the hippocampus and the primary visual cortex was decreased ().

Can We Link Perception And Cognition? | Slate Star Codex

The history of our evolving understanding of the pathophysiology of psychiatric disorders is complex and affected by the changing concepts of psychiatric disease and advances in neuroscience,. Furthermore, as Thomas Kuhn has emphasized, science is not a neutral observer, and new conceptual approaches are generally met with considerable resistance. This was clearly the case with regard to the role of NMDARs in the pathophysiology of schizophrenia. Early research viewed hypofunction of NMDARs through the lens of the widely held dopamine hypothesis of schizophrenia, whereas recent research has focused on the NMDAR deficit as element, albeit important, in dysfunctional cortical circuit with dopamine-mediated psychosis, a downstream consequence. Nevertheless, 30 years ago, investigators were already touting glutamatergic neurotransmission as a worthy target for drug development to treat schizophrenia,, a strategy that has only recently been embraced by the pharmaceutical industry.,

Full Recovery from Schizophrenia? | Brain Blogger

Some evidence from animal studies suggests that specific components of the NMDA receptor unit (e.g., NMDAR2D) may be developmentally regulated (). In one of the first studies of NMDA receptor subunits in schizophrenia, Akbarian et al. () presented data that suggested a regional deficit in NMDA subunit density in brain tissue of schizophrenics. The expression patterns of five NMDA receptor subunits (NMDAR1/NMDAR2 [A-D]) were measured in postmortem prefrontal, parieto-temporal and cerebellar cortical tissue of schizophrenics (N=15) and age-, gender- and autolysis time-matched controls (N=15). A significant 53% proportional increase in NMDAR2D subunit mRNA levels was found in prefrontal areas of schizophrenics, but no significant changes were observed in the expression patterns of the other NMDA receptor subunits. Other brain regions were similar to those in controls, and no medication effects were apparent. Furthermore, some data suggest that NMDAR2D may be necessary for the formation of specific neuronal connections that are, at least in part, mediated by NMDA receptors (). Special kinetic properties of postsynaptic NMDA receptors containing the NR2D polypeptide may effect postsynaptic depolarization when presynaptic activity is reduced (). These data support the hypothesis by Akbarian et al. () that an increase in NMDAR2D subunits could reflect a compensatory response to decreased function (hypofrontality) in prefrontal cortical regions of the schizophrenic brain.

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