Abstract
Antagonists of N-methyl-D-aspartate receptors (NMDAR) have psychotomimetic effects in humans and are used to model schizophrenia in animals. We used high-density electrophysiological recordings to assess the effects of acute systemic injection of an NMDAR antagonist (MK-801) on ensemble neural processing in the medial prefrontal cortex of freely moving rats. Although MK-801 increased neuron firing rates and the amplitude of gamma-frequency oscillations in field potentials, the synchronization of action potential firing decreased and spike trains became more Poisson-like. This disorganization of action potential firing following MK-801 administration is consistent with changes in simulated cortical networks as the functional connections among pyramidal neurons become less clustered. Such loss of functional heterogeneity of the cortical microcircuit may disrupt information processing dependent on spike timing or the activation of discrete cortical neural ensembles, and thereby contribute to hallucinations and other features of psychosis induced by NMDAR antagonists.
Highlights
N-methyl-D-aspartate receptor (NMDAR) antagonists, such as ketamine and MK-801, have acute psychotomimetic effects in healthy subjects, including hallucinations, thought disorder, and impairments of working memory, pre-pulse inhibition, and attention [1,2,3,4,5]
The behavioral effects of NMDAR antagonists are suppressed by the concomitant application of clinically used antipsychotics [13,14], suggesting that their mechanisms of action might be relevant to the pathophysiology of schizophrenia
Administration of MK801 significantly increased c-band power in the field potential (FP) signals recorded within the mPFC (Figure 2 B-C; two-tailed t-test; t(4) = 5.31, p,0.006), consistent with previous reports [5,43]
Summary
N-methyl-D-aspartate receptor (NMDAR) antagonists, such as ketamine and MK-801, have acute psychotomimetic effects in healthy subjects, including hallucinations, thought disorder, and impairments of working memory, pre-pulse inhibition, and attention [1,2,3,4,5]. The prefrontal cortex (PFC) is one of the cortical regions most consistently implicated in the etiology of schizophrenia This is supported by structural and functional neuroimaging [15,16,17], post-mortem studies of schizophrenic patients [18,19], and the dependence of cognitive functions disrupted in schizophrenia, such as working memory and set-shifting, on the integrity of PFC (reviewed by [20]). Previous studies of NMDAR antagonist effects on neural activity in the rodent medial PFC have shown increased firing rates of putative pyramidal neurons and decreased firing rate of putative interneurons, leading to a state of cortical disinhibition [21]. We used high density electrophysiology to assess how rodent cortical dynamics are affected by acute NMDAR antagonism in order to elucidate possible functional deficits associated with cortical disinhibition
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