Regionally different responses of GABAergic interneuron populations to a NMDA receptor antagonist challenge with MK-801 and an antipsychotic “rescue therapy“ in an animal model of psychosis

Some behavioral symptoms and neuropathological features also found in genuine schizophrenia, like numerical alterations of GABAergic interneurons, could be emulated in an animal model of psychosis based on prolonged, low-dose exposure to the N-methyl-D-aspartate NMDA-receptor antagonist MK-801. By immunohistochemistry directed against calcium-binding proteins, specific for interneuronal subtypes we examined distinct subpopulations of GABAergic interneurons and their spatial distribution throughout different brain regions, focussing on the limbic system. Compared to saline control, animals having received MK-801 exhibited a markedly decreased density of hippocampal parvalbumin-positive interneurons in the dentate gyrus, whereas the calretinin-immunoreactivity was significantly increased in the dentate gyrus of the hippocampal formation. NeuN-expressing cells representing adult neurons where almost unaffected, as were glial cells expressing GFAP, thus excluding unspecific neurotoxic effects of MK-801. Co-administration of the antipsychotic drug haloperidol mitigated the reduction of parvalbumine-positive interneurons in the hippocampal formation, but led to a marked reduction in the density of prefrontal parvalbumin expressing interneurons, when comparing with MK-801 or haloperidol treatment alone. These data show that a prolonged application of NMDA-receptor antagonist could, in part, mimic some neuropathologic findings in human schizophrenia, thus strengthening the idea that chronic, low-dose NMDA-receptor antagonism in animals is a viable approach in mimicking aspects of schizophrenia. Moreover, this study provides further evidence for regional differences in the response of GABAergic interneurons to NMDA-receptor antagonism and antipsychotic treatment.