Quercetin Relieves D-Amphetamine induced Manic-like Behavior through
Activating TREK-1 Potassium Channels in Mice
Abstract
Background and Purpose: Quercetin is a prominent neuroprotective
compound from flavonoids. Previous studies found it may relieve
psychiatric disorders, cognition deficits, and memory dysfunction
through anti-oxidation and/or radical scavenging mechanisms. In
addition, Quercetin also was found to modulate the physiological
function of a few types of ion channels. However, the detailed ionic
mechanisms of quercetin’s bioeffect remain unknown. Experimental
Approach: We examined the effect neuronal activities changes in
prefrontal cortex (PFC) and its ionic mechanisms upon quercetin
application by using GCaMP calcium imaging and patch clamp in acute
brain slices. Then we explored the potential ionic mechanism of
quercetin on D-amphetamine induced manic-like using c-fos staining and
the open field behavior test. Key Results: Quercetin reduced calcium
influx triggered by PFC pyramidal neuronal activity. This effect was
caused by increasing the rheobase of neuronal firing through decreasing
membrane resistance upon quercetin treatment. Spadin, a TREK-1 potassium
channel (a two-pore-domain background potassium channel) inhibitor,
could block the effect of quercetin on the membrane resistance and
neuronal firing. And also, Spadin can block the neural protective
effects of quercetin. In addtion, intraperitoneal injection of quercetin
could relieve the manic hyperlocomotion of the mice induced by
D-amphetamine, which can be partially alleviated by Spadin. Conclusion
and Implications: Our results demonstrated that TREK-1 channel is a
novel target on quercetin treatment, which could contribute to both the
neuroprotection and anti-manic-like effects.