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

Author(s): 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 | Abstract: 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 pl 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.