Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory

Abstract

The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson’s disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABAA receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory.

Taste Impairments in a Parkinson’s Disease Model Featuring Intranasal Rotenone Administration in Mice

“…In our previous study, we also found that with the intranasal administration of rotenone (0.35 mg/kg) for 1 week, mice exhibited a mild impaired memory of conditioned taste aversion to bitter taste [24].…”

“…This result was corroborated by the experiments using the microinjection of 6-OHDA into the IC, which reduced the existence of axon terminals. In our previous study, the 1w-Rot group also showed impaired conditioned taste aversion memory to bitter taste and simultaneously the alteration of the synaptic plasticity of layer V pyramidal neurons in the IC [ 24 ]. Although these studies provided the controversial results in the synaptic plasticity of the IC for the differences between the experimental conditions (e.g., stimulating/recording sites, recording methods, and in vitro / vivo ), the change of the synaptic plasticity by TH-ir fiber loss of the IC probably caused the impaired taste memory.…”

“…These mice were randomly divided into the rotenone ( n = 70) and vehicle ( n = 70) groups, housed with a 12-h light/dark cycle at a constant room temperature (20–24°C), and given ad libitum access to food. We previously described the method employed for the intranasal administration of rotenone [ 24 ]. Briefly, the rotenone (Sigma-Aldrich, MO, USA) was first dissolved in 100% dimethyl sulfoxide (DMSO; Fujifilm Wako Pure Chemical Corporation, Osaka, Japan) to derive a stock solution at a concentration of 0.1 M. The stock solution was then diluted with distilled water (DW) just before the administration to the mice to prevent any degradation of rotenone in the DW.…”

“…In addition, prolonging the rotenone exposure to 2 weeks caused degeneration of the CA neuronal fibers in the SN without neural loss [ 23 ]. In our previous study, we also found that with the intranasal administration of rotenone (0.35 mg/kg) for 1 week, mice exhibited a mild impaired memory of conditioned taste aversion to bitter taste [ 24 ]. Interestingly, the impaired taste associative memory was also shown in the genetic fly model of PD ( DJ-1 mutant fly), accompanied by the reduction of taste sensitivity [ 25 ].…”

The Intriguing Contribution of Hippocampal Long-Term Depression to Spatial Learning and Long-Term Memory

“…We propose that without LTD, memory generalization can occur that confounds disambiguation of similar experiences ( Figure 3 ). This possibility is supported by findings that animals with impairments in LTD quickly forget conditioned taste aversion and consume more of the conditioned substance than controls ( Toyoda et al, 2020 ), are unable to learn the platform location in a water maze and show long-term memory deficits in a Barnes maze ( Rocchetti et al, 2015 ). They also display enhanced freezing behavior, in the absence of foot shock, weeks after context-dependent conditioning ( Navarrete et al, 2019 ).…”