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The Journal of Neuroscience, June 14, 2006, 26(24):6573-6582; doi:10.1523/JNEUROSCI.1497-06.2006

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Neurobiology of Disease
Concomitant Deficits in Working Memory and Fear Extinction Are Functionally Dissociated from Reduced Anxiety in Metabotropic Glutamate Receptor 7-Deficient Mice

Zsuzsanna Callaerts-Vegh,¹ Tom Beckers,² Simon M. Ball,³ Frank Baeyens,² Patrick F. Callaerts,⁴ John F. Cryan,⁵ Elek Molnar,³ and Rudi D'Hooge¹

¹Laboratory of Biological Psychology and ²Center for Learning Psychology and Experimental Psychopathology, Department of Psychology, University of Leuven, B-3000 Leuven, Belgium, ³Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol BS8 1TD, United Kingdom, ⁴Laboratory of Developmental Genetics, Flemish Interuniversity Institute of Biotechnology–University of Leuven, Center for Human Genetics, B-3000 Leuven, Belgium, and ⁵Nervous System Research, Novartis Institutes for BioMedical Sciences, Novartis Pharma AG, CH-4002 Basel, Switzerland

Correspondence should be addressed to Dr. Rudi D'Hooge, Laboratory of Biological Psychology, Tiensestraat 102, 3000 Leuven, Belgium. Email: rudi.dhooge{at}psy.kuleuven.be

Metabotropic glutamate receptor 7 (mGluR7), a receptor with a distinct brain distribution and a putative role in anxiety, emotional responding, and spatial working memory, could be an interesting therapeutic target for fear and anxiety disorders. mGluR7-deficient (mGluR7^–/–) mice showed essentially normal performance in tests for neuromotor and exploratory activity and passive avoidance learning but prominent anxiolytic behavior in two anxiety tests. They showed a delayed learning curve during the acquisition of the hidden-platform water maze, and three interspersed probe trials indicated that mGluR7^–/– mice were slower to acquire spatial information. Working memory in the water maze task and the radial arm maze was impaired in mGluR7^–/– mice compared with mGluR7^+/+. mGluR7^–/– mice also displayed a higher resistance to extinction of fear-elicited response suppression in a conditioned emotional response protocol. In a non-fear-based water maze protocol, mGluR7^–/– mice displayed similar delayed extinction. These observed behavioral changes are probably not attributable to changes in AMPA or NMDA receptor function because expression levels of AMPA and NMDA receptors were unaltered. Extinction of conditioned fear is an active and context-dependent form of inhibitory learning and an experimental model for therapeutic fear reduction. It appears to depend on glutamatergic and higher-level brain functions similar to those involved in spatial working memory but functionally dissociated from those that mediate constitutional responses in anxiety tests.

Key words: metabotropic glutamate receptors; fear and anxiety; fear extinction; conditioned emotional response; learning and memory; operant

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Received Nov. 10, 2005; accepted April 25, 2006.

Correspondence should be addressed to Dr. Rudi D'Hooge, Laboratory of Biological Psychology, Tiensestraat 102, 3000 Leuven, Belgium. Email: rudi.dhooge{at}psy.kuleuven.be

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