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.
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.
Wöhrl
Robert
R
Institute of Neurophysiology, Johannes Müller Centre of Physiology, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany.
Eisenach
Sven
S
Manahan-Vaughan
Denise
D
Heinemann
Uwe
U
von Haebler
Dorothea
D
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D066298:In Vitro Techniques; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000145:classification / Q000187:drug effects*; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate