Schizophrenia is mostly a progressive psychiatric illness. Although cognitive changes in chronic schizophrenia have been investigated, little is known about the consequences of a single psychotic episode on memory mechanisms and formation. We investigated changes in hippocampal long-term potentiation (LTP) and spatial memory in a rat model of an acute psychotic episode. Application of NMDA receptor antagonists, such as MK801 (dizolcilpine) in rats, have been shown to give rise to an acute and short-lasting behavioral state, which mirrors many symptoms of schizophrenia. Furthermore, NMDA antagonist-intake in humans elicits symptoms of schizophrenia such as hallucinations, delusions, and affective blunting. We therefore treated animals with a single systemic injection of MK801 (5 mg/kg). Increased stereotypy, locomotion, and ataxia were evident immediately after MK801-treatment, with effects disappearing within 24 h. MK801-treatment caused a disruption of prepulse inhibition of the acoustic startle reflex, 1 day but not 7 or 28 days after treatment. These effects were consistent with the occurrence of an acute psychotic episode. LTP was profoundly impaired in freely moving rats 7 days after MK801 application. Four weeks after treatment, a slight recovery of LTP was seen, however marked deficits in long-term spatial memory were evident. These data suggest that treatment with MK801 to generate an acute psychotic episode in rats, gives rise to grave disturbances in synaptic plasticity and is associated with lasting impairments with the ability to form spatial memory.

For the first time, evidence is provided that dysfunctional activation of frontal lobe networks in smokers is also present in long term abstainers.

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.

The entorhinal cortex (EC) innervates area CA1 and the subiculum directly via the portion of the perforant path, which originates from EC layer III cells referred to as direct cortical input (dCI), and indirectly via the trisynaptic loop through the dentate gyrus and area CA3. The dCI is of great importance as it mediates positional information for activation of place cells that is not prevented after interrupting information flow from area CA3 to CA1. In this study, we investigated the effects of low-frequency stimulation of the dCI on homo- and heterosynaptic plasticity in area CA1 and tested for the contribution of NMDA, GABA(A), GABA(B), kainate and group I mGlu receptors. We demonstrate that 1 Hz stimulation of the dCI induces homosynaptic long-term depression (LTD) and that 1 Hz stimulation of the dCI induces a long-lasting augmentation of stratum radiatum-induced population spikes in area CA1 (heterosynaptic long-term potentiation). Additionally we show that homosynaptic effects depend on activation of GABA(B) and kainate receptors, whereas the heterosynaptic effects are GABA(A) and mGlu receptor dependent.