Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating
| Autor: | Qi Dai, Abdul Rezzak Hamzeh, Marquis P. Vawter, Nayna Sanathara, Lamees Alhassen, Lucas Pauluk, Jasmine Sakr, Amal Alachkar, Xuejie Wang, Ryan F. Yoshimura, Olivier Civelli, Anton Schulmann, Wedad Alhassen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Melanin-concentrating hormone Genome-wide association study Medical and Health Sciences Regular Research Articles chemistry.chemical_compound Mice 0302 clinical medicine Receptors 80 and over 2.1 Biological and endogenous factors Medicine Pharmacology (medical) Receptors Somatostatin Prefrontal cortex Child Psychiatry Aged 80 and over Mice Knockout Hypothalamic Hormones Behavior Animal AcademicSubjects/SCI01870 Middle Aged Sensory Gating Psychiatry and Mental health Mental Health medicine.anatomical_structure Schizophrenia Child Preschool Female Somatostatin Adult AcademicSubjects/MED00415 Adolescent Knockout Neuropeptide Prefrontal Cortex 03 medical and health sciences Young Adult Fetus Behavioral and Social Science Genetics Animals Humans Preschool Aged Pharmacology Melanins Behavior Memory Disorders Animal business.industry Psychology and Cognitive Sciences Neurosciences Infant medicine.disease Brain Disorders Melanin-concentrating hormone receptor Dorsolateral prefrontal cortex Disease Models Animal Pituitary Hormones 030104 developmental biology chemistry Disease Models business Neuroscience 030217 neurology & neurosurgery Hormone |
| Zdroj: | International Journal of Neuropsychopharmacology The international journal of neuropsychopharmacology, vol 23, iss 1 |
| ISSN: | 1469-5111 1461-1457 |
| Popis: | Background Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone (MCH) system in modulating emotional and cognitive functions. Genome wide association (GWA) studies revealed a potential association between the MCH receptor (MCHR1) gene locus and schizophrenia and the largest GWA study conducted to date shows a credible GWA. Methods We analyze MCHR1 and pro-melanin concentrating hormone (PMCH) RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the MCH system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of MCH expressing neurons using a Cre-inducible diphtheria toxin (iDTR) system. Results MCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (FDR p< 0.05, CommonMind and PsychEncode combined datasets, N = 901) while PMCH 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 PMCH neurons increased repetitive behavior and produced a deficit in sensorimotor gating. Conclusions Our study indicates that early disruption of the MCH 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 MCH may lead to a therapeutic target for early prevention of schizophrenia. |
| Databáze: | OpenAIRE |
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