DECODING THE LINK AMONG SCHIZOPHRENIA, METABOLIC SYNDROME, AND THE SEROTONIN/MELATONIN PATHWAY USING THE MK-801 MOUSE MODEL
Authors: Shkodra Atea , Barzon Benedetta , Cherchi Laura , Ferroni Carolina Giulia , Nasini Sofia , De Gregorio Danilo , Fadda Paola , Paribello Pasquale , Manchia Mirko , Squassina Alessio , Pisanu Claudia , Bosia Marta , Comai *Stefano 
Published: February 2025

Abstract

Background
Schizophrenia, a complex and debilitating psychiatric disorder, is often comorbid with metabolic syndrome, intertwining the realms of mental health and physiological dysregulation. Serotonin (5-HT), a neurotransmitter derived from tryptophan and implicated in both psychiatric and metabolic regulation, could be a pivotal player in this interplay. Moreover, 5-HT is the precursor of the neuromodulator melatonin (MLT), which is also an important regulator of brain function and metabolism, as well as the circadian system. Dysregulation of the circadian system has been associated with both schizophrenia and metabolic disturbances. However, the specific mechanisms linking schizophrenia, metabolic disturbances, 5-HT, and MLT are still unknown.

Aims & Objectives
To unravel the possible neurobiological link among schizophrenia, metabolic disturbances and the tryptophan to 5-HT and MLT pathway.

Method
We investigated the activity of dorsal raphe nucleus (DRN) 5-HT neurons in anesthetized mice using single-unit in-vivo electrophysiology in mice considered melatonin proficient (C3H/HeN strain) and melatonin deficient (C57BL/6J strain). We induced metabolic dysfunction by subjecting them to a 10- week high-fat diet (HFD) and schizophrenia-like symptoms by injecting the non-competitive NMDA receptor antagonist MK-801 (0.3 mg/Kg, intraperitoneal). Severity of schizophrenia-like symptoms in the different experimental groups were assessed in the open field test.

Results
As expected, in the open field test, we found that in mice of both strains MK-801 induced an increase in the locomotor activity, a measure of the severity of psychotic symptoms. Of interest, the increase in locomotor activity due to MK-801 treatment was lower in animals of both strains undergoing the HFD diet compared to those fed a normal diet. Moreover, while C57BL/6J mice fed a HFD independently of the MK-801 treatment spent less time in the centre of the open field than those fed a normal diet, no diet-induced differences were observed in C3H/HeN mice. These behavioural changes were paralleled by significant effects strain and diet dependent in the DRN 5-HT neural activity. In melatonin-deficient C57BL/6J mice, DRN 5-HT firing activity was higher in HFD than in normal diet mice independently of MK-801 treatment. The coefficient of variation (COV) of the 5-HT neurons, a measure of their regularity, in animals treated with vehicle was higher in HFD than in normal diet animals. In contrast, no effect of diet on the COV was seen in mice treated with MK-801. In melatonin-proficient C3H/HeN mice, DRN 5-HT spontaneous firing activity was also higher in HFD than in normal diet mice independently of MK-801 treatment. However, independently on the diet, MK-801 treatment was reducing DRN 5-HT neural activity. No effect of either diet or MK-801 treatment was observed on the COV of DRN 5-HT.

Discussion & Conclusion
These preliminary findings show that 5-HT neurotransmission may be impaired in schizophrenia when in comorbidity with metabolic disturbances, but this impairment is dependent on the physiological function of the MLT system.