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

Authors

  • Robert Wöhrl,

    1. Institute of Neurophysiology, Johannes Müller Centre of Physiology, Charité - Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany
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    • *

      R.W. and S.E. contributed equally to this work.

  • Sven Eisenach,

    1. Institute of Neurophysiology, Johannes Müller Centre of Physiology, Charité - Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany
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    • *

      R.W. and S.E. contributed equally to this work.

  • Denise Manahan-Vaughan,

    1. Learning and Memory Research, Medical Faculty, Ruhr University Bochum, Germany
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  • Uwe Heinemann,

    1. Institute of Neurophysiology, Johannes Müller Centre of Physiology, Charité - Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany
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  • Dorothea Von Haebler

    1. Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Dr U. Heinemann, as above.
E-mail: uwe.heinemann@charite.de

Abstract

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 µm) 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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