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The Journal of Neuroscience, June 18, 2008, 28(25):6459-6472; doi:10.1523/JNEUROSCI.0412-08.2008

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Behavioral/Systems/Cognitive
Inducible cAMP Early Repressor Acts as a Negative Regulator for Kindling Epileptogenesis and Long-Term Fear Memory

Nobuhiko Kojima,^1,2 Gilyana Borlikova,¹ Toshiro Sakamoto,¹ Kazuyuki Yamada,³ Toshio Ikeda,⁴ Shigeyoshi Itohara,⁴ Hiroaki Niki,⁵ and Shogo Endo¹

¹Unit for Molecular Neurobiology of Learning and Memory, Okinawa Institute of Science and Technology, Uruma, 904-2234, Japan, ²Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan, ³Research Resources Center and ⁴Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, 351-0198, Japan, and ⁵Department of Psychology, School of Human and Social Sciences, Saitama Institute of Technology, Fukaya, 369-0293, Japan

Correspondence should be addressed to Dr. Shogo Endo, Unit for Molecular Neurobiology of Learning and Memory, Okinawa Institute of Science and Technology, 12-22 Suzaki, Uruma, 904-2234, Japan. Email: sendo{at}oist.jp

Long-lasting neuronal plasticity as well as long-term memory (LTM) requires de novo synthesis of proteins through dynamic regulation of gene expression. cAMP-responsive element (CRE)-mediated gene transcription occurs in an activity-dependent manner and plays a pivotal role in neuronal plasticity and LTM in a variety of species. To study the physiological role of inducible cAMP early repressor (ICER), a CRE-mediated gene transcription repressor, in neuronal plasticity and LTM, we generated two types of ICER mutant mice: ICER-overexpressing (OE) mice and ICER-specific knock-out (KO) mice. Both ICER-OE and ICER-KO mice show no apparent abnormalities in their development and reproduction. A comprehensive battery of behavioral tests revealed no robust changes in locomotor activity, sensory and motor functions, and emotional responses in the mutant mice. However, long-term conditioned fear memory was attenuated in ICER-OE mice and enhanced in ICER-KO mice without concurrent changes in short-term fear memory. Furthermore, ICER-OE mice exhibited retardation of kindling development, whereas ICER-KO mice exhibited acceleration of kindling. These results strongly suggest that ICER negatively regulates the neuronal processes required for long-term fear memory and neuronal plasticity underlying kindling epileptogenesis, possibly through suppression of CRE-mediated gene transcription.

Key words: fear conditioning; amygdala kindling; CRE-mediated gene transcription; ICER; CREB; immediate early genes

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Received Jan. 30, 2008; revised April 8, 2008; accepted April 28, 2008.

Correspondence should be addressed to Dr. Shogo Endo, Unit for Molecular Neurobiology of Learning and Memory, Okinawa Institute of Science and Technology, 12-22 Suzaki, Uruma, 904-2234, Japan. Email: sendo{at}oist.jp

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