Preliminary study on the time-correlation changes in brain neurotransmitters of mice exposed to mushroom toxin ibotenic acid

Ruanxian Dai¹Zhantao Duan²Bin Han³Guobing Chen³Fuping Wang³Zhuange Shi³Xian Zhou³Haifei Song³Li Ma³Qiang Meng^3*

• ¹Kunming University of Science and Technology, Kunming, China
• ²The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
• ³The First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China

Background: Mushroom poisoning represents a significant food safety issue globally, particularly neurotoxic mushroom poisoning, which raises considerable concern due to its potential to induce central nervous system symptoms. Ibotenic acid is identified as the primary neurotoxin associated with this form of poisoning; however, the underlying mechanisms of its neurotoxicity remain poorly understood.Objective: This study aims to systematically evaluate the effects of ibotenic acid exposure across three consecutive key time points, from intoxication to recovery, on neurotransmitters related to the GABA/ Glutamic-Acid, dopaminergic, serotonergic, and cholinergic systems in five brain regions: the cerebral cortex, hippocampus, striatum, brainstem, and cerebellum.Methods: Through behavioral tests, we assessed the effects of ibotenic acid exposure on voluntary activities and learning and memory functions in mice. Additionally, we analyzed the changes in neurotransmitter concentrations across different brain regions using targeted metabolomics. Results:： Behavioural results indicated that the total movement distance and speed in the open field test were significantly reduced, while the resting time was prolonged in the ibotenic acid-exposed group (P < 0.0001). The results of targeted metabolomics demonstrated that, compared to the control group, levels of glutamic acid in the hippocampus and brainstem significantly decreased after 4 hours of ibotenic acid exposure (P < 0.05, P < 0.001). Additionally, Epinephrine levels in the cerebral cortex decreased at 20 minutes (P < 0.05), while tyrosine levels in the brainstem and cerebellum decreased after 4 hours (P < 0.05). In the brainstem region, the tryptophan levels in each exposure group decreased significantly compared with the 4-hour exposure group (P < 0.01), and brainstem choline levels significantly decreased (P < 0.05). Conversely, homovanillic acid levels in the brainstem increased (P < 0.01).Preliminary studies have demonstrated that acute exposure to ibotenic acid inhibits motor activity but does not significantly affect learning and memory in mice. Exposure to ibotenic acid induces alterations in GABA/Glutamic-Acid, dopaminergic, serotonergic, and neurotransmitters associated with the cholinergic system in the brains of mice, with the most pronounced changes occurring in the brainstem region, exhibiting time-dependent and region-specific effects. This study offers new insights into the neurotoxic mechanisms of ibotenic acid.