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NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex.

ABSTRACT: Cognitive deficits associated with frontal lobe dysfunction are a determinant of long-term disability in schizophrenia and are not effectively treated with available medications. Clinical studies show that many aspects of these deficits are transiently induced in healthy individuals treated with N-methyl-D-aspartate (NMDA) antagonists. These findings and recent genetic linkage studies strongly implicate NMDA receptor deficiency in schizophrenia and suggest that reversing this deficiency is pertinent to treating the cognitive symptoms of schizophrenia. Despite the wealth of behavioral data on the effects of NMDA antagonist treatment in humans and laboratory animals, there is a fundamental lack of understanding about the mechanisms by which a general state of NMDA deficiency influences the function of cortical neurons. Using ensemble recording in freely moving rats, we found that NMDA antagonist treatment, at doses that impaired working memory, potentiated the firing rate of most prefrontal cortex neurons. This potentiation, which correlated with expression of behavioral stereotypy, resulted from an increased number of irregularly discharged single spikes. Concurrent with the increase in spike activity, there was a significant reduction in organized bursting activity. These results identify two distinct mechanisms by which NMDA receptor deficiency may disrupt frontal lobe function: an increase in disorganized spike activity, which may enhance cortical noise and transmission of disinformation; and a decrease in burst activity, which reduces transmission efficacy of cortical neurons. These findings provide a physiological basis for the NMDA receptor deficiency model of schizophrenia and may clarify the nature of cortical dysfunction in this disease.

SUBMITTER: Jackson ME

PROVIDER: S-EPMC420417 | biostudies-literature | 2004 Jun

REPOSITORIES: biostudies-literature

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NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex.

Jackson Mark E ME Homayoun Houman H Moghaddam Bita B

Proceedings of the National Academy of Sciences of the United States of America 20040524 22

Cognitive deficits associated with frontal lobe dysfunction are a determinant of long-term disability in schizophrenia and are not effectively treated with available medications. Clinical studies show that many aspects of these deficits are transiently induced in healthy individuals treated with N-methyl-D-aspartate (NMDA) antagonists. These findings and recent genetic linkage studies strongly implicate NMDA receptor deficiency in schizophrenia and suggest that reversing this deficiency is perti ...[more]

PMID: 15159546

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Project description: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 ?-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency ?-oscillations (LF?) and high-frequency ?-oscillations (HF?) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HF? and LF? in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LF? (? 34 Hz at 32°C) in layer V and HF? (? 54 Hz) in layer III of the same cortical column. In controls, HF? and LF? were independent, and pyramidal neurons recorded in layer III were entrained by HF?, but not by LF?. Sub-anesthetic concentrations of ketamine selectively decelerated HF? by 22 Hz (EC(50)=2.7 ?M), to match the frequency of LF? in layer V. This caused phase coupling of the two ?-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LF? in layer V. PCP similarly decelerated HF? by 22 Hz (EC(50)=0.16 ?M), causing cross-layer phase coupling of ?-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HF?, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HF?. The NMDA receptor hypofunction-induced phase coupling of the normally independent ?-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 HF? and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HF? could be the target for improved antipsychotic therapy.

Dataset Information

NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex.

Publications

NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex.

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