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The Journal of Neuroscience, February 1, 2006, 26(5):1562-1570; doi:10.1523/JNEUROSCI.4142-05.2006

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Behavioral/Systems/Cognitive
Hippocampal CA3 NMDA Receptors Are Crucial for Adaptive Timing of Trace Eyeblink Conditioned Response

Yasushi Kishimoto,^1,2,3 Kazu Nakazawa,^3,4 Susumu Tonegawa,⁴ Yutaka Kirino,² and Masanobu Kano¹

¹Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan, ²Laboratory of Neurobiophysics, School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0003, Japan, ³National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4405, and ⁴Howard Hughes Medical Institute, The Picower Center for Learning and Memory, RIKEN–Massachusetts Institute of Technology Neuroscience Research Center, Center for Cancer Research, and Departments of Biology and Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307

Correspondence should be addressed to Dr. Masanobu Kano, Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Email: mkano{at}cns.med.osaka-u.ac.jp

Classical conditioning of the eyeblink reflex is a simple form of associative learning for motor responses. To examine the involvement of hippocampal CA3 NMDA receptors (NRs) in nonspatial associative memory, mice lacking an NR1 subunit selectively in adult CA3 pyramidal cells [CA3-NR1 knock-out (KO) mice] were subjected to eyeblink conditioning paradigms. Mice received paired presentations of an auditory conditioned stimulus (CS) and a periorbital shock unconditioned stimulus (US). With repeated presentation of the CS followed by the US, wild-type mice learned to blink in anticipation of the US before its onset. We first confirmed that wild-type mice require an intact hippocampus in the trace version of eyeblink conditioning in which the CS and US do not overlap, creating a stimulus-free time gap of 500 ms. Under the same condition, CA3-NR1 KO mice successfully acquired conditioned responses (CRs) during the 10 d acquisition sessions, whereas the extinction of CRs was impaired on the first day of extinction sessions. Importantly, CA3-NR1 KO mice were impaired in the formation of an adaptively timed CR during the first five trials in the daily acquisition sessions. The aberrantly timed CR was also observed in the extinction sessions in accordance with the impaired extinction of CRs. These results indicate that CA3-NR1 KO mice are unable to rapidly retrieve adaptive CR timing, suggesting that CA3 NRs play a crucial role in the memory of adaptive CR timing in trace conditioning.

Key words: NMDA receptor; hippocampus; area CA3; eyeblink conditioning; nonspatial associative memory; mouse

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Received Sept. 28, 2005; revised Dec. 11, 2005; accepted Dec. 11, 2005.

Correspondence should be addressed to Dr. Masanobu Kano, Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Email: mkano{at}cns.med.osaka-u.ac.jp

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