Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

Valentina Wiescholleck

doi:10.3389/fnint.2013.00012

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.

Highlights

The uncompetitive N -methyl-D-aspartate (NMDA) receptor antagonist, MK801, is frequently used in neuroscientific research
N-methyl-D-aspartate receptor (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
We explored whether the loss of long-term potentiation (LTP) triggered by NMDAR antagonism in this animal model of psychosis persists for long periods, as a clue to the substrate for disturbed cognition as the disease develops

Summary

Introduction

The uncompetitive N -methyl-D-aspartate (NMDA) receptor antagonist, MK801, is frequently used in neuroscientific research. Its unique kinetics and ability to induce all kinds of schizophrenia symptoms in humans (Krystal et al, 1994; Lahti et al, 2001) has promoted it into one of the drugs of choice in modeling schizophrenia in animals (Rujescu et al, 2006). Acute treatment with MK801 is believed to efficiently mimic a single acute psychosis-like episode in rats that may emulate first-episode psychosis (Kehrer et al, 2007; Wöhrl et al, 2007; Manahan-Vaughan et al, 2008a). It induces long-lasting dysfunctions, within the cognitive domain. Long-lasting impairments in spatial learning in rodents after a single MK801-treatment that persisted for up to months have been reported (Wozniak et al, 1996; Lukoyanov and Paula-Barbosa, 2000; Manahan-Vaughan et al, 2008a,b).

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