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NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex.

ABSTRACT: Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPARs) contributed background depolarization to sustain network firing. In contrast, many Response cells were sensitive to AMPAR blockade and increased firing after systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer's disease profoundly impair cognition.

SUBMITTER: Wang M

PROVIDER: S-EPMC3584418 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex.

Wang Min M Yang Yang Y Wang Ching-Jung CJ Gamo Nao J NJ Jin Lu E LE Mazer James A JA Morrison John H JH Wang Xiao-Jing XJ Arnsten Amy F T AF

Neuron 20130201 4

Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persi ...[more]

PMID: 23439125

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Project description:ImportanceThe extent of dorsolateral prefrontal cortex (DLPFC) plasticity in Alzheimer disease (AD) and its association with working memory are not known.ObjectivesTo determine whether participants with AD had impaired DLPFC plasticity compared with healthy control participants, to compare working memory between participants with AD and controls, and to determine whether DLPFC plasticity was associated with working memory.Design, setting, and participantsThis cross-sectional study included 32 participants with AD who were 65 years or older and met diagnostic criteria for dementia due to probable AD with a score of at least 17 on the Mini-Mental State Examination and 16 age-matched control participants. Participants were recruited from a university teaching hospital from May 2013 to October 2016.Main outcomes and measuresPlasticity of the DLPFC measured as potentiation of cortical-evoked activity using paired associative stimulation (a combination of peripheral nerve electrical stimulation and transcranial magnetic stimulation) combined with electroencephalography. Working memory was assessed with the n-back task (1- and 2-back) and measured using the A' statistic.ResultsAmong the 32 participants with AD, 17 were women and 15 were men (mean [SD] age, 76.3 [6.3] years); among the 16 controls, 8 were men and 8 were women (mean [SD] age, 76.4 [5.1] years). Participants with AD had impaired DLPFC plasticity (mean [SD] potentiation, 1.18 [0.25]) compared with controls (mean [SD] potentiation, 1.40 [0.35]; F1,44 = 5.90; P = .02; between-group comparison, Cohen d = 0.77; P = .01). Participants with AD also had impaired performances on the 1-back condition (mean [SD] A' = 0.47 [0.30]) compared with controls (mean [SD] A' = 0.96 [0.01]; Cohen d = 1.86; P < .001), with similar findings for participants with AD on the 2-back condition (mean [SD] A' = 0.29 [0.2]) compared with controls (mean [SD], A' = 0.85 [0.18]; Cohen d = 2.83; P < .001). Plasticity of DLPFC was positively associated with working memory performance on the 1-back A' (parameter estimate B [SE] = 0.32 [0.13]; standardized β = 0.29; P = .02) and 2-back A' (B [SE] = 0.43 [0.15]; β = 0.39; P = .006) across both groups after controlling for age, education, and attention.Conclusions and relevanceThis study demonstrated impaired in vivo DLPFC plasticity in patients with AD. The findings support the use of DLPFC plasticity as a measure of DLPFC function and a potential treatment target to enhance DLPFC function and working memory in patients with AD.

Dataset Information

NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex.

Publications

NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex.

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