Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type?

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ID: 86632
2019
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Abstract
Hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs), whether caused by endogenous factors like auto-antibodies or mutations, or by pharmacological or genetic manipulations, produces a wide variety of deficits which overlap with-but do not precisely match-the symptom spectrum of schizophrenia. In order to understand how NMDAR hypofunction leads to different components of the syndrome, it is necessary to take into account which neuronal subtypes are particularly affected by it in terms of detrimental functional alterations. We provide a comprehensive overview detailing findings in rodent models with cell type-specific knockout of NMDARs. Regarding inhibitory cortical cells, an emerging model suggests that NMDAR hypofunction in parvalbumin (PV) positive interneurons is a potential for this disease. PV interneurons display a selective vulnerability resulting from a combination of genetic, cellular, and environmental factors that produce pathological multi-level positive feedback loops. Central to this are two antioxidant mechanisms-NMDAR activity and perineuronal nets-which are themselves impaired by oxidative stress, amplifying disinhibition. However, NMDAR hypofunction in excitatory pyramidal cells also produces a range of schizophrenia-related deficits, in particular maladaptive learning and memory recall. Furthermore, NMDAR blockade in the thalamus disturbs thalamocortical communication, and NMDAR ablation in dopaminergic neurons may provoke over-generalization in associative learning, which could relate to the positive symptom domain. Therefore, NMDAR hypofunction can produce schizophrenia-related effects through an action on various different circuits and cell types.
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Authors Bygrave, Alexei M;Kilonzo, Kasyoka;Kullmann, Dimitri M;Bannerman, David M;Kätzel, Dennis;
Journal Frontiers in psychiatry
Year 2019
DOI
10.3389/fpsyt.2019.00835
URL
Keywords
schizophrenia psychosis ketamine mk-801 n-methyl-d-aspartate receptor n-methyl-d-aspartate receptor hypofunction catatonic schizophrenia parvalbumin

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