Expression of the Circadian Clock Gene Period2 in the Hippocampus: Possible Implications for Synaptic Plasticity and Learned Behaviour

Abstract

Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2) gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour.

Day differences in the cortisol awakening response predict day differences in synaptic plasticity in the brain

“…These dual pathways mean it can fine tune sensitivity of the adrenal cortex to adrenocorticotrophic hormone (the secretagogue for cortisol) and make it ideally suited to relay messages to the periphery from the master CLOCK. Glucocorticoids are known to affect peripheral CLOCKs in almost all organs and tissues by influencing the expression of several clock-related genes, which in turn have been shown to modify synaptic plasticity (Wang et al, 2009). This means that the circadian pattern of glucocorticoid secretion (and as indicated by this study the CAR in particular) can affect function in a sustained way over the day, not just by the influence of ambient levels e.g.…”

“…We used this measure as a representative indicator of effects caused by any factor that affects the whole brain. We hypothesised that one function of the CAR is to regulate the sensitivity of synaptic plasticity, known to be modulated by peripheral CLOCK genes (Wang et al, 2009) during the coming day and that this could be one mechanism whereby the CAR could influence a wide range of behaviours. We predicted that day-to-day variation in the CAR would correlate with day-to-day variation in rTMS-induced synaptic plasticity of the motor cortex.…”

Membrane Currents, Gene Expression, and Circadian Clocks

“…In Drosophila period null-mutant flies, which are behaviorally arrhythmic, the daily rhythm of excitability of pacemaker neurons is also eliminated . Even outside of central clocks, neurons in the medial habenula express rhythms in electrical activity that could be measured in a brain slice and these rhythms are lost in the Cry1/2 dKO (Sakhi et al 2014a,b); although, in the hippocampus, the loss of Per2 did not alter excitability of CA1 neurons (Wang et al 2009). Still, the finding in the habenula raises the possibility that the molecular clock may influence the membrane properties of neurons throughout the nervous system.…”

Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice

“…Wang et al, (28) showed that Per2 mRNA and protein expression varied across the 24 hour cycle in the hippocampus.…”