Expression of parvalbumin and glutamic acid decarboxylase-67 after acute administration of MK-801. Implications for the NMDA hypofunction model of schizophrenia

Romón, Tamara; Mengod, Guadalupe; Adell, Albert

doi:10.1007/s00213-011-2268-6

Cited by 34 publications

(19 citation statements)

References 56 publications

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“…There is some evidence of the impact of NMDAR antagonists on interneurons, particularly on those targeting the soma of pyramidal neurons (Romón et al, 2011; Rotaru et al, 2011). However, little is known about the effects that NMDAR blockade can exert on other types of interneurons, like those targeting the distal segments of the dendrites of pyramidal neurons.…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

Pérez-Rando

Castillo-Gómez

Guirado

et al. 2017

Front. Cell. Neurosci.

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N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB). We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

Pérez-Rando

Castillo-Gómez

Guirado

et al. 2017

Front. Cell. Neurosci.

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“…This is relevant as schizophrenia is thought to be a chronic developmental disease, in which both reduced NMDA-receptor function and compensatory changes likely contribute to observed phenotypes. This limitation is more applicable to ketamine where repeated administration is required for PV interneuron disruption as opposed to MK801 where only a single dose is required (Behrens and Sejnowski, 2009; Romon et al). …”

Section: Discussionmentioning

confidence: 99%

NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia

Saunders

Gandal

Siegel

2012

Neurobiology of Disease

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Rationale There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently used pharmacological models of schizophrenia, recreate deficits in electrophysiological markers of disturbed brain circuits that are thought to underlie the illness. Furthermore, this study characterizes the specificity of these differences across the frequency spectrum so as to help identify the nature of selective circuit abnormalities that mediate each oscillatory response as relevant to schizophrenia. Design Mouse EEG was recorded during exposure to repeated auditory stimuli after injection of either vehicle or drug. The dose-response relationship for each electrophysiological measure was determined for ketamine and MK-801. Time-frequency analyses were performed to assess baseline, total, and evoked power and intertrial coherence (ITC) at low (5–10 Hz) and high (35–80 Hz)-frequencies. Results High frequency evoked and total power was decreased by MK-801 and ketamine in a dose-dependent fashion. High frequency baseline power was increased by MK-801 and ketamine in a dose-dependent fashion. Similar to evoked power, high frequency inter-trial coherence was dose-dependently decreased by both drugs. Low frequency ITC was only decreased by ketamine. Conclusions Both ketamine and MK-801 cause alterations in high-frequency baseline (noise), total (signal), and evoked (signal) power resulting in a loss of high frequency SNR that is thought to primarily reflect local circuit activity. These changes indicate an inappropriate increase in baseline activity, which can also be interpreted as non-task related activity. Ketamine induced a loss of intertrial coherence at low frequencies, indicating a loss of consistency in low-frequency circuit mechanisms. As a proportion of baseline power, both drugs had a relative shift from low to high frequencies, reflecting a change in the balance of brain activity from coordination of global regions to a pattern of discoordinated, autonomous local activity. These changes are consistent with a pattern of fragmented regional brain activity seen in schizophrenia.

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“…16, 17 In addition, in terms of certain schizophrenia-relevant GABAergic markers, the dentate gyrus has been shown to react first to systemically applied MK801 as compared with all other hippocampal subfields and brain regions. 31 Both electrodes were made of polyurethane-coated stainless steel wire. A cannula was implanted in the lateral cerebral ventricle (0.5 mm posterior to bregma, 1.6 mm lateral to the midline, 5.6 mm length, 0.8 mm diameter, 4 mm depth) to enable injections.…”

Section: Methodsmentioning

confidence: 99%

PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis

Wiescholleck

Manahan‐Vaughan

2012

Transl Psychiatry

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Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl--aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP.

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Expression of parvalbumin and glutamic acid decarboxylase-67 after acute administration of MK-801. Implications for the NMDA hypofunction model of schizophrenia

Abstract: These findings indicate that acute administration of a NMDA antagonist delineate a pattern of changes in GABAergic markers different from those observed in postmortem tissue in schizophrenia inasmuch as only deficits in parvalbumin (but not GAD(67)) were seen.

Cited by 34 publications

References 56 publications

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia

PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis

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