Circadian photoperiod alters TREK‐1 channel function and expression in dorsal raphe serotonergic neurons via melatonin receptor 1 signaling

Abstract

Seasonal day length has been linked to the prevalence of mood disorders, and however, the mechanisms underlying this relationship remain unknown. Previous work in our laboratory has shown that developmental exposure to seasonal photoperiods has enduring effects on the activity of mouse dorsal raphe serotonergic neurons, their intrinsic electrical properties, as well as on depression and anxiety‐related behaviors. Here we focus on the possible ionic mechanisms that underlie the observed programming of the electrophysiological properties of serotonin neurons, focusing on the twin‐pore K + channels TREK‐1 and TASK‐1 that set resting membrane potential and regulate excitability. Pharmacological inhibition of TREK‐1 significantly increased spike frequency in Short and Equinox photoperiods, but did not further elevate the firing rate in slices from Long photoperiod mice, suggesting that TREK‐1 function is reduced in Long photoperiods. In contrast, inhibition of TASK‐1 resulted in increases in firing rates across all photoperiods, suggesting that it contributes to setting excitability, but is not regulated by photoperiod. We then quantified Kcnk2 mRNA levels specifically in dorsal raphe 5‐HT neurons using triple‐label RNAscope. We found that Long photoperiod significantly reduced levels of Kcnk2 in serotonin neurons co‐expressing Tph2, and Pet‐1. Photoperiodic effects on the function and expression of TREK‐1 were blocked in melatonin 1 receptor knockout (MT‐1KO) mice, consistent with previous findings that MT‐1 signaling is necessary for photoperiodic programming of dorsal raphe 5‐HT neurons. Taken together these results indicate that photoperiodic regulation of TREK‐1 expression and function plays a key role in photoperiodic programming the excitability of dorsal raphe 5‐HT neurons.

Photoperiod integration in C3H rd1 mice

“…53,54 On another level, melatonin has been showed to play a role in the photoperiod-dependent regulation of serotonin neurotransmission by the dorsal raphe nucleus, which could impact locomotor activity and mood in response to seasonal variations. 55,56 Taken together, these studies suggest that both melatonin and ipRGCs changes could take part in the modulation of the SCN activity/locomotor activity to photoperiod variation. Besides, the idea that ipRGCs could take part in seasonal adaptation has also been mentioned in a recent review.…”

Melatonin exerts neuroprotective effects in mice with spinal cord injury by activating the Nrf2/Keap1 signaling pathway via the MT2 receptor

“…Recent studies suggest that MT1 receptors are primarily associated with biological circadian rhythms. For instance, Giannoni-Guzmán et al ( 46 ) found that a prolonged photoperiod resulted in decreased co-expression levels of Tph2 and Pet-1 in 5-HT neurons, and this modulatory effect of the photoperiod on TREK-1 was lost in MT1 knockout mice. Li reported that melatonin reduces the expression of Nox2 and Nox4, thereby decreasing ROS levels and attenuating the inflammatory response in mice with ischemic stroke through the activation of MT2 receptors ( 47 ).…”

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

“…Knockout also increased risk of epileptic seizures triggered by kainite or pentylenetetrazol; the mutant animals showed increased morbidity as well as increased spike amplitude and frequency, based on electroencephalography [56]. Administering spadin to mice did not reduce infarct size following focal ischemia or alleviate kainate-induced seizures [63] TREK-1 in serotonergic neurons of the dorsal raphe has recently been implicated in the circadian photoperiod [64]. Longer photoperiods may reduce TREK-1 function, since pharmacological inhibition of TREK-1 significantly increased spike frequency in animals exposed to short or equinox photoperiods but not in animals exposed to long photoperiods, which expressed lower levels of the channel [64].…”