The role of PPARβ/δ in the regulation of glutamatergic signaling in the hamster suprachiasmatic nucleus

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and function as transcription factors that regulate gene expression in numerous biological processes. Although the PPARβ/δ subtype is highly expressed in the brain, its physiological roles in neuronal function remain to be elucidated. In this study, we examined the presence of PPARβ/δ in the master circadian clock of the Syrian hamster and investigated its putative functional role in this structure. In mammals, the central circadian clock, located in the suprachiasmatic nucleus (SCN), is entrained by the light-dark (LD) cycle via photic6 signals conveyed by a direct pathway whose terminals release glutamate. Using immunocytochemical and qRT-PCR analysis, we demonstrated that the rhythmic expression of PPAR β/δ within the SCN of hamsters raised under an LD cycle was detectable only at the transcriptional level when the hamsters were maintained under constant darkness (DD). The increase in the number of immunoreactive PPARβ/δ cells observed under DD after light stimulation during the early subjective night (CT14), but not during the subjective day (CT06), demonstrated that the expression of PPARβ/δ can be up-regulated according to the photosensitive phase of the circadian clock. All of the PPARβ/δ-positive cells in the SCN also expressed the glutamate receptor NMDAR1. Moreover, we demonstrated that at the photosensitive point (CT14), the administration of L-16504, a specific agonist of PPARβ/δ, amplified the phase delay of the locomotor response induced by a light pulse. Taken together, these data suggest that PPARβ/δ activation modulates glutamate release that mediates entrainment of the circadian clock by light.

Temporal Regulation of GABAAReceptor Subunit Expression: Role in Synaptic and Extrasynaptic Communication in the Suprachiasmatic Nucleus

“…2, 4) is a phenomenon that has also been reported in other studies (described below) on transcript-protein expression relationships in the SCN. Peroxisome proliferator-activated receptor β/δ mRNA and protein display rhythmicity in the SCN of animals housed in LD cycles, but in DD, mRNA expression remains rhythmic whereas protein expression does not (Challet et al, 2013). Further evidence that transcript and protein rhythms can be uncoupled comes from a recent SCN proteome study that analyzed 2112 proteins.…”

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

“…It is important to remember, however, that mRNA rhythms can be uncoupled from protein rhythms in the SCN (Challet et al, 2013; Chiang et al, 2014), suggesting that rhythms in protein may prove more informative than rhythms in mRNA levels. We recently found that the ratio of the δ subunit (contained in the GABA A -TONIC receptor) to the γ 2 subunit (contained in the GABA A -PHASIC receptor) is rhythmic in the SCN.…”

PPARs Integrate the Mammalian Clock and Energy Metabolism

“…Recently, Challet et al observed oscillations in PPAR β / δ expression in hamster SCN. Administration of PPAR β / δ agonist L-16504 amplified the delay phase of locomotor response induced by a light pulse [54], indicating that PPAR β / δ may play a role in circadian behavior. In another recent paper, Liu et al revealed a PPAR β / δ -dependent diurnal oscillation of de novo lipogenesis in mouse liver [55].…”