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

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 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.

Enhanced Dopamine-Dependent Hippocampal Plasticity after Single MK-801 Application

“…In line with previous findings (Wöhrl et al, 2007), LTP at SC-CA1 synapses was impaired in MK-801-treated rats 24 h post injection (control: 1.69±0.11, n ¼ 8, po0.001; MK-801: 1.11 ± 0.11, n ¼ 8; Figure 1a and c). In sharp contrast, LTP could be readily induced at CA1-SUB synapses (control: 2.23±0.30, n ¼ 11, po0.01; MK-801: 2.58±0.49, n ¼ 9, po0.05; Figure 1d and f).…”

“…Hippocampal dysfunction in and after psychosis has been suggested to include subfield-specific alterations in synaptic plasticity (Tamminga et al, 2012;Wiescholleck and Manahan-Vaughan, 2013;Wöhrl et al, 2007). The CA1 and SUB act as major relay stations in the hippocampus-VTA loop.…”

Antagonism of glutamate receptors in the CA1 to perirhinal cortex projection prevents long-term potentiation and attenuates levels of brain-derived neurotrophic factor

“…The intensity of stimulus was then set at a level that evoked a fEPSP slope of 50-60% of the maximum. This level is similar to that we have used before Commins, 2005, 2006) on the CA1 and subicular to EC pathway and is similar to that used by other authors (Wöhrl et al, 2008) and Cousens and Otto (1998) on the CA1-perirhinal pathway.…”

Frequency-dependent changes in synaptic plasticity and brain-derived neurotrophic factor (BDNF) expression in the CA1 to perirhinal cortex projection

“…The intensity of stimulus was then set at a level that evoked a fEPSP slope of 50-60% of the maximum. This level is similar to that we have used before Commins, 2005, 2006) on the CA1 and subicular to EC pathway, Cousens and Otto (1998) on the CA1-perirhinal pathway and to that used by other authors in area CA1 (Wöhrl et al, 2007).…”