Period1 gates the circadian modulation of memory‐relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK

Abstract

Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response elementbinding protein (CREB) are central to the circadian (~24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memoryrelevant hippocampal signaling pathways. We found that in wildtype mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1 À/À ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1 À/À mice, however, pP90RSK remained perinuclear. A coimmunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1.

Circadian Rhythms in Fear Conditioning: An Overview of Behavioral, Brain System, and Molecular Interactions

“…Together, this can explain why activation of the MAPK pathway, facilitating hippocampus-dependent spatial memory formation, becomes especially effective in stimulating CREB phosphorylation when expression levels of PER1 are high during the light phase. This matches the circadian pattern of contextual fear memory strength, inducing the highest freezing levels when both fear conditioning training and testing are performed during the light phase [90]. The behavioral time pattern coincides with a peak in activation of MAPK pathway components upstream of P-CREB during the light phase, namely, the second messenger cAMP and the phosphorylation forms of the kinases MEK1/2 and ERK1/2 [91].…”

“…First, molecular signaling pathways relevant for the consolidation of long-term fear memories are modulated by genes that drive the internal clock [89, 90], and deficiency in clock genes results in impairments in contextual fear memory [88]. Other learning types addressing hippocampal functions as well as cellular models of learning that lastingly alter synaptic plasticity are similarly modulated by the internal clock (see, e.g., [9, 10] for recent reviews).…”

“…Indeed, variations in spatial memory strength are dependent on the daytime of testing and may relate to circadian rhythms of CREB phosphorylation [89]. A possible mechanism for such gating effects of clock genes on the MAPK pathway has been recently described by Rawashdeh et al [90]. In their model, PER1 is suggested to form a complex with the MAPK-activated ribosomal S6 kinase (p90RSK), which translocates to the nucleus upon neuronal activation.…”

“…Acetylcholine release is increased in the hippocampus during contextual fear conditioning training and correlates with freezing levels measured briefly after [117]. However, acetylcholine levels also correspond to general locomotor activity and are therefore high during the active, dark phase within the prefrontal cortex and hippocampus [117, 118], whereas the fear memory strength is increased during conditioning and testing in the inactive phase [51, 90]. Performance in a passive avoidance task is more successful during the active dark phase, but it is diminished by blocking the degeneration of acetylcholine.…”

“…In addition, fear memory consolidation strength is modulated by serotonin (5HT) and acetylcholine (ACh), which show circadian variations in amygdala and/or hippocampal tissue levels as well [112, 117]. (c) On the molecular level, it has been shown in hippocampal neurons that different components of the MAPK pathway display a circadian activation profile, with peaks during the light phase for the second messenger cAMP (dark red), the kinase ERK1/2 (light green), the transcription factor CREB (dark green), and the protein translation initiation factor eIF4E (light red) [90, 91, 93]. Moreover, the nuclear translocation of p90RSK, a kinase that activates CREB and modulates translation, is regulated by the clock protein PER1, thereby modulating transcriptional activation of CREB-dependent downstream proteins [90].…”