Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets

Elisabeth Lang; Anne S. Mallien; Andrei Nicolae Vasilescu; Dimitri Hefter; Alessia Luoni; Marco A. Riva; Stefan Borgwardt; Rolf Sprengel; Undine E. Lang; Peter Gass; Dragos Inta

doi:10.1016/j.neubiorev.2017.08.012

Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets

Elisabeth Lang, Anne S. Mallien, Andrei Nicolae Vasilescu, Dimitri Hefter, Alessia Luoni, Marco A. Riva, Stefan Borgwardt, Rolf Sprengel, Undine E. Lang, Peter Gass, Dragos Inta^*

^*Corresponding author for this work

Department of Psychiatry, Psychosomatics and Psychotherapie

32 Citations (Scopus)

Abstract

A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.

Original language	English
Journal	Neuroscience and Biobehavioral Reviews
Volume	84
Pages (from-to)	352-358
Number of pages	7
ISSN	0149-7634
DOIs	https://doi.org/10.1016/j.neubiorev.2017.08.012
Publication status	Published - 01.2018

Funding

This work was supported by grants from the Deutsche Forschungsgemeinschaft (DI427/11-1) to D.I. and P.G., the Ingeborg St?nder Foundation to D.I. and R.S. and the Research Fund of the UPK Basel to D.I. This work was supported by grants from the Deutsche Forschungsgemeinschaft ( DI427/11-1 ) to D.I. and P.G., the Ingeborg Ständer Foundation to D.I. and R.S. and the Research Fund of the UPK Basel to D.I.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

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10.1016/j.neubiorev.2017.08.012

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title = "Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets",

abstract = "A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.",

author = "Elisabeth Lang and Mallien, \{Anne S.\} and Vasilescu, \{Andrei Nicolae\} and Dimitri Hefter and Alessia Luoni and Riva, \{Marco A.\} and Stefan Borgwardt and Rolf Sprengel and Lang, \{Undine E.\} and Peter Gass and Dragos Inta",

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doi = "10.1016/j.neubiorev.2017.08.012",

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T1 - Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets

AU - Lang, Elisabeth

AU - Mallien, Anne S.

AU - Vasilescu, Andrei Nicolae

AU - Hefter, Dimitri

AU - Luoni, Alessia

AU - Riva, Marco A.

AU - Borgwardt, Stefan

AU - Sprengel, Rolf

AU - Lang, Undine E.

AU - Gass, Peter

AU - Inta, Dragos

PY - 2018/1

Y1 - 2018/1

N2 - A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.

AB - A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.

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EP - 358

JO - Neuroscience and Biobehavioral Reviews

JF - Neuroscience and Biobehavioral Reviews

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Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets

Abstract

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UN SDGs

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