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ASN NEURO (2009) 1(3):art:e00012.doi:10.1042/AN20090020

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Expression of the circadian clock gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour

Louisa M‑C Wang*, Joanna M Dragich*†, Takashi Kudo*, Irene H Odom*, David K Welsh‡§, Thomas J O'Dell∥ and Christopher S Colwell*¹

^*Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024-1759, U.S.A.
^†Department of Neurology, Columbia University, New York City, NY 10032, U.S.A.
^‡Departmentof Psychiatry and Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, U.S.A.
^§Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, U.S.A.
^∥Department of Physiology, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024-1759, U.S.A.

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.

Key words: circadian rhythm, fear conditioning, hippocampus, long-term potentiation, memory, Period 2

Abbreviations: ACSF, artificial cerebrospinal fluid, CA, cornu ammonis, CREB, cAMP-response-element-binding protein, CS, conditioned stimulus, CT, circadian time, DD, constant darkness, DG, dentate gyrus, DTT, dithiothreitol, ERK, extracellular-signal-regulated kinase, fEPSP, field excitatory post-synaptic potential, IHC, immunohistochemistry, IO, input/output, ISH, in situ hybridization, LD, light/dark, LTP, long-term potentiation, MAPK, mitogen-activated protein kinase, p-CREB, phosphorylated CREB, Per2, Period 2, p-ERK, phosphorylated ERK, poly(A)⁺ RNA, polyadenylated RNA, PTX, picrotoxin, SC, Schaffer collaterals, SCN, suprachiasmatic nucleus, US, unconditioned stimulus, WT, wild-type, ZT, zeitgeber time

¹To whom correspondence should be addressed (email ccolwell@mednet.ucla.edu).

Received 17 March 2009/31 March 2009; accepted 3 April 2009

Published as ASN NEURO Immediate Publication 28 May 2009, doi:10.1042/AN20090020

©2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.