Expression of the NR2B-NMDA receptor trafficking complex in prefrontal cortex from a group of elderly patients with schizophrenia

Kristiansen, Lars V.; Bakir, Buket; Haroutunian, Vahram; Meador‐Woodruff, James H.

doi:10.1016/j.schres.2010.02.1069

Cited by 47 publications

(43 citation statements)

References 87 publications

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“…Although the total cellular expression of NR2 proteins is not consistently altered in the cortex of schizophrenics, the trafficking of NR2B subunit-containing NMDA receptors to their presynaptic and postsynaptic locations is impaired (Kristiansen et al, 2010). In the chronic low-dose MK-801-treated rat model, parvalbumin-expressing interneurons have a reduced NMDA receptor expression (Xi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Hypofunction Phase Couples Independent γ-Oscillations in the Rat Visual Cortex

Anver

Ward

Magony

et al. 2010

Neuropsychopharmacol

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Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N-methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the γ-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency γ-oscillations (LFγ) and high-frequency γ-oscillations (HFγ) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HFγ and LFγ in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LFγ (∼ 34 Hz at 32°C) in layer V and HFγ (∼ 54 Hz) in layer III of the same cortical column. In controls, HFγ and LFγ were independent, and pyramidal neurons recorded in layer III were entrained by HFγ, but not by LFγ. Sub-anesthetic concentrations of ketamine selectively decelerated HFγ by 22 Hz (EC(50)=2.7 μM), to match the frequency of LFγ in layer V. This caused phase coupling of the two γ-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LFγ in layer V. PCP similarly decelerated HFγ by 22 Hz (EC(50)=0.16 μM), causing cross-layer phase coupling of γ-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HFγ, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HFγ. The NMDA receptor hypofunction-induced phase coupling of the normally independent γ-generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HFγ and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HFγ could be the target for improved antipsychotic therapy.

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Section: Discussionmentioning

confidence: 99%

NMDA Receptor Hypofunction Phase Couples Independent γ-Oscillations in the Rat Visual Cortex

Anver

Ward

Magony

et al. 2010

Neuropsychopharmacol

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“…Furthermore alterations in associated transporter and regulatory proteins of the NMDAR subunits has been reported in schizophrenia, particularly associated with the NR2B subunit (Kristiansen et al, 2010). For example, molecules in the NR2B trafficking complex are dysregulated in schizophrenia patients, with an increase in CASK and mLin7C mRNA in the prefrontal cortex and an increase in mLin7A and APBA mRNA and decrease in CASK and mLin7C protein in the anterior cingulate cortex (Kristiansen et al, 2010).…”

Section: Nmda Receptor Subunits and Schizophreniamentioning

confidence: 99%

“…For example, molecules in the NR2B trafficking complex are dysregulated in schizophrenia patients, with an increase in CASK and mLin7C mRNA in the prefrontal cortex and an increase in mLin7A and APBA mRNA and decrease in CASK and mLin7C protein in the anterior cingulate cortex (Kristiansen et al, 2010). While human post-mortem data supports that NMDARs and their subunits are altered in schizophrenia, whether they be increased or decreased in brain regional 1908, displayed increased locomotor activity (10-30mg/kg) and impaired response inhibition (1-10mg/kg) but no disruption to PPI (1-10mg/kg) (Higgins et al, 2003).…”

Section: Nmda Receptor Subunits and Schizophreniamentioning

confidence: 99%

Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia

Geddes

Huang

Newell

2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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. (2011) Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin 1 and their role in schizophrenia, Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 35, no. 4, 1 June 2011 pp. 896-904. Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin 1 and their role in schizophrenia AbstractSchizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the N-methyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However little is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via altering the balance of NR2 subunits during early development, could influence NRG1 signalling. Tables : 1 2 Abstract Schizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the Nmethyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However not much is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via the altering...

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“…23 Trafficking of proteins to and from microdomains such as the PSD is tightly regulated, and accumulating evidence suggests that this process may be disrupted in schizophrenia. [52][53][54] We found a decrease in EAAT1 protein in the MD nucleus, and a corresponding decrease in EAAT1 mRNA in cells enriched for astrocytes. We previously reported diminished EAAT1 protein levels in the frontal cortex and superior temporal gyrus in schizophrenia.…”

Section: Discussionmentioning

confidence: 65%

Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons?

et al. 2015

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Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Converging evidence suggests that abnormalities in the astroglial glutamate transporter localization and function may underlie a disease mechanism with pathological glutamate spillover as well as alterations in the kinetics of perisynaptic glutamate buffering and uptake contributing to dysfunction of thalamo-cortical circuits in schizophrenia. We explored this hypothesis by performing cell- and region-level studies of EAAT1 and EAAT2 expression in the mediodorsal nucleus of the thalamus in an elderly cohort of subjects with schizophrenia. We found decreased protein expression for the typically astroglial-localized glutamate transporters in the mediodorsal and ventral tier nuclei. We next used laser-capture microdissection and quantitative polymerase chain reaction to assess cell-level expression of the transporters and their splice variants. In the mediodorsal nucleus, we found lower expression of transporter transcripts in a population of cells enriched for astrocytes, and higher expression of transporter transcripts in a population of cells enriched for relay neurons. We confirmed expression of transporter protein in neurons in schizophrenia using dual-label immunofluorescence. Finally, the pattern of transporter mRNA and protein expression in rodents treated for 9 months with antipsychotic medication suggests that our findings are not due to the effects of antipsychotic treatment. We found a compensatory increase in transporter expression in neurons that might be secondary to a loss of transporter expression in astrocytes. These changes suggest a profound abnormality in astrocyte functions that support, nourish and maintain neuronal fidelity and synaptic activity.

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Expression of the NR2B-NMDA receptor trafficking complex in prefrontal cortex from a group of elderly patients with schizophrenia

Cited by 47 publications

References 87 publications

NMDA Receptor Hypofunction Phase Couples Independent γ-Oscillations in the Rat Visual Cortex

NMDA Receptor Hypofunction Phase Couples Independent γ-Oscillations in the Rat Visual Cortex

Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia

Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons?

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