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The Journal of Neuroscience, February 28, 2007, 27(9):2212-2223; doi:10.1523/JNEUROSCI.3954-06.2007

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Behavioral/Systems/Cognitive
Inhibition of Kainate Receptors Reduces the Frequency of Hippocampal Theta Oscillations

John R. Huxter,^1,3 Larissa E. Zinyuk,¹ Eva v. L. Roloff,¹ Vernon R. J. Clarke,¹ Nigel P. Dolman,² Julia C. A. More,² David E. Jane,² Graham L. Collingridge,¹ and Robert U. Muller^1,4

Departments of ¹Anatomy and ²Pharmacology, Medical Research Council Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, United Kingdom, ³Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Oxford OX1 3TH, United Kingdom, and ⁴Health Science Center at Brooklyn, State University of New York, Brooklyn, New York 11203

Correspondence should be addressed to Dr. John R. Huxter, Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK. Email: john.huxter{at}pharm.ox.ac.uk

We investigated the role of kainate receptors in the generation of theta oscillations using (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-yl-methyl)pyrimidine-2,4-dione (UBP304), a novel, potent and highly selective antagonist of GLU_K5-containing kainate receptors. EEG and single-unit recordings were made from the dorsal hippocampus of awake, freely moving rats trained to forage for food. Bilateral intracerebroventricular injections of UBP304 (2.0 µl, two times; 2.08 mM) caused a clear (25%) reduction in theta frequency that was dissociable from behavioral effects of the drug. The locations of firing fields of principal cells in the hippocampal formation were generally preserved, but both field firing rates and the precision of field organization decreased. UBP304 lowered the frequency of the theta modulation of hippocampal interneuron discharge, accurately matching the reduced frequency of the theta field oscillation. UBP308 [(R)-1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-yl-methyl)pyrimidine-2,4-dione], the inactive enantiomer of UBP304, caused none of these effects. Our results suggest that GLU_K5 receptors have an important role in modulating theta activity. In addition, the effects on cellular responses provide both insight into the mechanisms of theta pacing, and useful information for models of temporal coding.

Key words: hippocampus; electrophysiology; place cells; EEG; GluR5; GLU_K5

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Received March 7, 2006; revised Nov. 17, 2006; accepted Nov. 21, 2006.

Correspondence should be addressed to Dr. John R. Huxter, Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK. Email: john.huxter{at}pharm.ox.ac.uk

This article has been cited by other articles:

				M. Goldin, J. Epsztein, I. Jorquera, A. Represa, Y. Ben-Ari, V. Crepel, and R. Cossart Synaptic Kainate Receptors Tune Oriens-Lacunosum Moleculare Interneurons to Operate at Theta Frequency J. Neurosci., September 5, 2007; 27(36): 9560 - 9572. [Abstract] [Full Text] [PDF]

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