Wöhrl R, Eisenach S, Manahan-Vaughan D, Heinemann U, von Haebler D. Acute and long-term effects of MK-801 on direct cortical input evoked homosynaptic and heterosynaptic plasticity in the CA1 region of the female rat. Eur J Neurosci 26: 2873-2883

Institute of Neurophysiology, Johannes Müller Centre of Physiology, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany.
European Journal of Neuroscience (Impact Factor: 3.18). 12/2007; 26(10):2873-83. DOI: 10.1111/j.1460-9568.2007.05899.x
Source: PubMed


We analysed acute and long-term effects of the N-methyl-d-aspartate receptor antagonist MK-801 on long-term heterosynaptic population spike depression (LTHPSD) evoked by high-frequency stimulation of the direct cortical input in female rat hippocampal slices to understand disturbances in cognitive functions associated with an acute phencyclidine-induced psychosis. High-frequency stimulation (HFS) of the direct cortical input (dCI) to cornu ammonis area 1 (CA1) induced homosynaptic long-term potentiation (LTP) while simultaneously evoking LTHPSD at the Schaffer collateral input. Animals treated with a single intraperitoneal application of MK-801 (5 mg/kg body weight) showed severe behavioural alterations for 24 h, although histological examination of CA1 did not reveal any morphological changes. However, after application of MK-801, homosynaptic LTP of the dCI was suppressed for up to 7 days and recovered within 4 weeks. Likewise, LTHPSD in response to HFS of the dCI to CA1 was abolished for at least 1 week post-treatment, with partial recovery occurring after 4 weeks. Homosynaptic LTP, induced by HFS of Schaffer collaterals, was also disturbed for at least 24 h, with recovery after 7 days. Remarkably, bath application of MK-801 (50 microM) converted LTHPSD, induced by dCI HFS, into persistent heterosynaptic long-term enhancement of stratum radiatum-evoked responses. The acute effects of MK-801 on synaptic plasticity seen in this study may contribute to the observed severe behavioural alterations and long-term effects and may explain some of the long-lasting symptoms remaining after an acute psychotic episode in humans.

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Available from: Dorothea von haebler, Mar 17, 2014
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    • "Specifically, at the concentration used in this study (5mg/kg), several studies found neurotoxic effects in certain brain areas (Fix et al., 1993; Farber et al., 1995), others found partly transient damage (Horváth et al., 1997) or even failed to detect any morphological changes at all after MK801-treatment (Wöhrl et al., 2007). Our quantitative analysis of viable cell numbers within the DG, EC, and RSC revealed no neurotoxic effects 4 weeks after MK801-treatment as compared to controls. "
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    ABSTRACT: Irreversible N-methyl-D-aspartate receptor (NMDAR) antagonism is known to provoke symptoms of psychosis and schizophrenia in healthy humans. NMDAR hypofunction is believed to play a central role in the pathophysiology of both disorders and in an animal model of psychosis, that is based on irreversible antagonism of NMDARs, pronounced deficits in hippocampal synaptic plasticity have been reported shortly after antagonist treatment. Here, we examined the long-term consequences for long-term potentiation (LTP) of a single acute treatment with an irreversible antagonist and investigated whether deficits are associated with memory impairments. The ability to express LTP at the perforant pathway - dentate gyrus synapse, as well as object recognition memory was assessed 1, 2, 3, and 4 weeks after a single treatment of the antagonist, MK801. Here, LTP in freely behaving rats was significantly impaired at all time-points compared to control LTP before treatment. Object recognition memory was also significantly poorer in MK801-treated compared to vehicle-treated animals for several weeks after treatment. Histological analysis revealed no changes in brain tissue. Taken together, these data support that acute treatment with an irreversible NMDAR-antagonist persistently impairs hippocampal functioning on behavioral, as well as synaptic levels. The long-term deficits in synaptic plasticity may underlie the cognitive impairments that are associated with schizophrenia-spectrum disorders.
    Frontiers in Integrative Neuroscience 03/2013; 7:12. DOI:10.3389/fnint.2013.00012
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    • "Induction of SDs in the CA1 region is independent of the origin of synaptic input Area CA1 receives input from area CA3, the contralateral hippocampus and the entorhinal cortex. To test whether SDs initiation after in-vivo albumin treatment is pathway specific, we stimulated the direct cortical pathway whose axons run through stratum lacunosum moleculare (Empson and Heinemann, 1995; Remondes and Schuman, 2002; Wöhrl et al., 2007a) , which transmits information from peri-and postrhinal cortex, and from lateral and medial entorhinal cortex to the hippocampus (Empson and Heinemann, 1995). Coactivation of other pathways was prevented by a cut through stratum oriens, pyramidale and radiatum between the subiculum and area CA1 with the stimulation of the stratum lacunosum on the subicular side of the cut (Fig. 3A).Induction of SDs using recurrent repetitive stimulation was observed under afSERUM perfusion in all slices (Fig. 3C, n = 10) obtained from in-vivo albumin treated animals (n = 4), but never in slices perfused with ACSF (n = 10 slices, 7 animals ) nor in slices from sham-operated animals (Fig. 3B, under afSERUM n = 5 slices, 4 animals). "
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    ABSTRACT: Recent studies showed that spreading depolarizations (SDs) occurs abundantly in patients following ischemic stroke and experimental evidence suggests that SDs recruit tissue at risk into necrosis. We hypothesized that BBB opening with consequent alterations of the extracellular electrolyte composition and extravasation of albumin facilitates generation of SDs since albumin mediates an astrocyte transcriptional response with consequent disturbance of potassium and glutamate homeostasis. Here we show extravasation of Evans blue-albumin complex into the hippocampus following cortical photothrombotic stroke in the neighboring neocortex. Using extracellular field potential recordings and exposure to serum electrolytes we observed spontaneous SDs in 80% of hippocampal slices obtained from rats 24h after cortical photothrombosis. Hippocampal exposure to albumin for 24h through intraventricular application together with serum electrolytes lowered the threshold for the induction of SDs in most slices irrespective of the pathway of stimulation. Exposing acute slices from naive animals to albumin led also to a reduced SD threshold. In albumin-exposed slices the onset of SDs was usually associated with larger stimulus-induced accumulation of extracellular potassium, and preceded by epileptiform activity, which was also observed during the recovery phase of SDs. Application of ifenprodil (3μM), an NMDA-receptor type 2 B antagonist, blocked stimulus dependent epileptiform discharges and generation of SDs in slices from animals treated with albumin in-vivo. We suggest that BBB opening facilitates the induction of peri-infarct SDs through impaired homeostasis of K(+).
    Neurobiology of Disease 07/2012; 48(3):495-506. DOI:10.1016/j.nbd.2012.06.024 · 5.08 Impact Factor
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    • "16, 17 Uncompetitive NMDAR-antagonists have been shown to induce psychotic symptoms in healthy humans and to exacerbate symptoms of schizophrenic patients.18, 19 After a single injection with MK801, rats display short-lasting transient behavioral aspects of psychosis-related behavior, such as disturbed pre-pulse inhibition of the acoustic startle response, disturbed stereotypy and increased ataxia.15, 16 This is followed by long-term impairments in both spatial memory and in LTP at the perforant path-dentate gyrus synapse of the hippocampus.16 "
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    ABSTRACT: 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-D-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.
    Translational Psychiatry 02/2012; 2(3):e89. DOI:10.1038/tp.2012.17 · 5.62 Impact Factor
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