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Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating

BACKGROUND: Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hor...

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Autores principales: Vawter, Marquis P, Schulmann, Anton, Alhassen, Lamees, Alhassen, Wedad, Hamzeh, Abdul Rezzak, Sakr, Jasmine, Pauluk, Lucas, Yoshimura, Ryan, Wang, Xuejie, Dai, Qi, Sanathara, Nayna, Civelli, Olivier, Alachkar, Amal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442395/
https://www.ncbi.nlm.nih.gov/pubmed/31563948
http://dx.doi.org/10.1093/ijnp/pyz051
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author Vawter, Marquis P
Schulmann, Anton
Alhassen, Lamees
Alhassen, Wedad
Hamzeh, Abdul Rezzak
Sakr, Jasmine
Pauluk, Lucas
Yoshimura, Ryan
Wang, Xuejie
Dai, Qi
Sanathara, Nayna
Civelli, Olivier
Alachkar, Amal
author_facet Vawter, Marquis P
Schulmann, Anton
Alhassen, Lamees
Alhassen, Wedad
Hamzeh, Abdul Rezzak
Sakr, Jasmine
Pauluk, Lucas
Yoshimura, Ryan
Wang, Xuejie
Dai, Qi
Sanathara, Nayna
Civelli, Olivier
Alachkar, Amal
author_sort Vawter, Marquis P
collection PubMed
description BACKGROUND: Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association. METHODS: We analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system. RESULTS: MCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P < .05, CommonMind and PsychEncode combined datasets, n = 901) while pro-melanin concentrating hormone is below the detection threshold. MCHR1 expression decreased with aging (P = 6.6E-57) in human dorsolateral prefrontal cortex. The deletion of MCHR1 was found to lead to behavioral abnormalities mimicking schizophrenia-like phenotypes: hyperactivity, increased stereotypic and repetitive behavior, social impairment, impaired sensorimotor gating, and disrupted cognitive functions. Conditional ablation of pro-melanin concentrating hormone neurons increased repetitive behavior and produced a deficit in sensorimotor gating. CONCLUSIONS: Our study indicates that early disruption of the melanin concentrating hormone system interferes with neurodevelopmental processes, which may contribute to the pathogenesis of schizophrenia. Further neurobiological research on the developmental timing and circuits that are affected by melanin concentrating hormone may lead to a therapeutic target for early prevention of schizophrenia.
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spelling pubmed-74423952020-08-25 Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating Vawter, Marquis P Schulmann, Anton Alhassen, Lamees Alhassen, Wedad Hamzeh, Abdul Rezzak Sakr, Jasmine Pauluk, Lucas Yoshimura, Ryan Wang, Xuejie Dai, Qi Sanathara, Nayna Civelli, Olivier Alachkar, Amal Int J Neuropsychopharmacol Regular Research Articles BACKGROUND: Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association. METHODS: We analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system. RESULTS: MCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P < .05, CommonMind and PsychEncode combined datasets, n = 901) while pro-melanin concentrating hormone is below the detection threshold. MCHR1 expression decreased with aging (P = 6.6E-57) in human dorsolateral prefrontal cortex. The deletion of MCHR1 was found to lead to behavioral abnormalities mimicking schizophrenia-like phenotypes: hyperactivity, increased stereotypic and repetitive behavior, social impairment, impaired sensorimotor gating, and disrupted cognitive functions. Conditional ablation of pro-melanin concentrating hormone neurons increased repetitive behavior and produced a deficit in sensorimotor gating. CONCLUSIONS: Our study indicates that early disruption of the melanin concentrating hormone system interferes with neurodevelopmental processes, which may contribute to the pathogenesis of schizophrenia. Further neurobiological research on the developmental timing and circuits that are affected by melanin concentrating hormone may lead to a therapeutic target for early prevention of schizophrenia. Oxford University Press 2019-09-30 /pmc/articles/PMC7442395/ /pubmed/31563948 http://dx.doi.org/10.1093/ijnp/pyz051 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of CINP. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Regular Research Articles
Vawter, Marquis P
Schulmann, Anton
Alhassen, Lamees
Alhassen, Wedad
Hamzeh, Abdul Rezzak
Sakr, Jasmine
Pauluk, Lucas
Yoshimura, Ryan
Wang, Xuejie
Dai, Qi
Sanathara, Nayna
Civelli, Olivier
Alachkar, Amal
Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
title Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
title_full Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
title_fullStr Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
title_full_unstemmed Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
title_short Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
title_sort melanin concentrating hormone signaling deficits in schizophrenia: association with memory and social impairments and abnormal sensorimotor gating
topic Regular Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442395/
https://www.ncbi.nlm.nih.gov/pubmed/31563948
http://dx.doi.org/10.1093/ijnp/pyz051
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