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Sci. Signal., 4 June 2013
Vol. 6, Issue 278, p. ec127
[DOI: 10.1126/scisignal.2004392]


Synaptic Plasticity Circadian Learning

Leslie K. Ferrarelli

Science Signaling, AAAS, Washington, DC 20005, USA

Learning and memory involve synaptic remodeling and are impaired by chronic stress. However, acute secretion of the stress hormone glucocorticoid improves learning in mice by promoting dendritic spine formation. Using in vivo imaging after motor coordination training on a rotating rod (rotarod) in mice overexpressing green fluorescent protein (GFP) in sensorimotor pyramidal neurons, Liston et al. showed that normal circadian oscillations in glucocorticoid secretion promote spine formation and maintenance through different mechanisms. Glucocorticoid oscillations were synchronous with the circadian clock, exhibiting a peak in the active phase and a trough in the inactive phase. Spine formation was increased in mice trained on the rotarod during the period of the glucocorticoid peak compared with mice trained during the period of the trough. Injection with corticosterone immediately after training increased spine formation in both groups, whereas suppression of endogenous glucocorticoid secretion with dexamethasone, a synthetic glucocorticoid that does not penetrate the blood-brain barrier at the doses used, blocked new spine formation in the group that was trained when the glucocorticoid peak would have occurred in the absence of dexamethasone. Corticosterone injection during the period when the glucocorticoid trough occurred destabilized newly formed spines, repetitive high-dose injections of corticosterone increased the elimination of preexisting spines, and either treatment impaired rotarod performance. Application of corticosterone directly to the cortex induced rapid spine formation, which was unaffected by the transcriptional inhibitor actinomycin D but blocked by mifepristone, an antagonist of the type II corticosteroid receptor [(glucocorticoid receptor (GR)], suggesting nontranscriptional regulation by the GR. Spine formation correlated with increased phosphorylation of the actin-stabilizing kinase LIMK1 and its substrate cofilin, in the cortex of untreated mice and those exposed to actinomycin D. Corticosterone-induced phosphorylation of LIMK1 or cofilin in primary neuronal cultures was eliminated if the GR was knocked down. Additionally, corticosterone-induced spine formation was prevented in LIMK1–/– mice. In contrast, spine elimination after corticosterone application was a delayed, cumulative process that was inhibited by actinomycin D but unaffected by mifepristone. Direct application of aldosterone, an agonist of the type I corticosteroid receptor [mineralocorticoid receptor (MR)], increased the rate of spine pruning, an effect that was blocked by cotreatment with actinomycin D. Both the basal and learning-induced rates of spine pruning were reduced by application of spironolactone, an MR antagonist. Together, the findings suggested that learning-induced spine formation is mediated by a GR- and kinase-dependent mechanism during periods when glucocorticoid peaks, whereas spine maintenance and memory retention require a period of low glucocorticoid abundance and are mediated by a separate MR- and transcription-dependent mechanism.

C. Liston, J. M. Cichon, F. Jeanneteau, Z. Jia, M. V. Chao, W.-B. Gan, Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Nat. Neurosci. 16, 698–705 (2013). [PubMed]

Citation: L. K. Ferrarelli, Circadian Learning. Sci. Signal. 6, ec127 (2013).

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