Lambda-Cyhalothrin Impairs Learning and Memory in Zebrafish by Disrupting Brain Energy Metabolism Coupled to Neurotransmitter Homeostasis via α-Ketoglutarate Depletion.

Abstract

Lambda-cyhalothrin (LCT) is a widely used type II pyrethroid insecticide commonly found in global aquatic environments. However, how it impairs cognitive function in non-target aquatic organisms at environmentally relevant concentrations remains poorly understood. In this study, adult zebrafish were chronically exposed to LCT at 0.1, 0.2, and 0.4 μg/L for 28 days. Behavioral tests, histopathological observations, multi-omics, and biochemical analyses were combined to explore the underlying neurotoxic mechanisms. Our results showed that exposure to 0.4 μg/L LCT significantly impaired spatial learning and memory in zebrafish and caused marked neuronal damage along with disrupted mitochondrial ultrastructure in the brain. LCT markedly inhibited key rate-limiting enzymes of glycolysis and the TCA cycle and blocked mitochondrial respiratory chain function, leading to insufficient ATP production and excessive ROS accumulation. Multi-omics integration revealed a severe depletion of cerebral α-ketoglutarate (α-KG) alongside inhibited α-ketoglutarate dehydrogenase (α-KGDH) activity and downregulated ogdh transcription. Critically, dietary supplementation with the cell-permeable α-KG analog dimethyl α-ketoglutarate (DM-KG) during LCT exposure restored brain α-KG levels, rescued TCA cycle flux and ATP production, attenuated oxidative stress, and recovered glutamate and GABA contents. These rescue experiments provide direct evidence that α-KG depletion is a key metabolic driver of LCT-induced disruption of energy metabolism and neurotransmitter homeostasis. While behavioral recovery was not assessed in the rescue experiment, these findings establish α-KG as a critical metabolic node in LCT neurotoxicity and offer a potential target for mitigating pyrethroid-induced neurological damage.