Neuroscience Memories of Receptors Endocytosed

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

A remarkably specific change in the behavior of mice is caused by a mutation of the 2 subunit of the -aminobutyric acid receptor (GABA_AR). GABA_ARs function at inhibitory synapses and are targets of behavior-altering benzodiazepines such as Valium^®. Tretter et al. created knock-in mice in which two sites of tyrosine phosphorylation in the 2 subunit were mutated to phenylalanine to prevent phosphorylation. In heterozygous mice expressing the altered receptor, accumulation of GABA_ARs at the cell membrane in the hippocampus, particularly in the CA3 region, was increased. This appeared to reflect alterations in endocytosis of the receptor resulting from reduced association of the mutant receptor with the clathrin-adaptor protein AP2. The size of inhibitory synapses in the CA3 region, as estimated by immunofluorescence confocal microscopy of puncta containing receptor subunits, was increased. The authors tested the behavior of the mutant mice in object recognition. Although the heterozygous mice could recognize an object that they had previously explored just as well as wild-type mice could, the mutant animals failed to recognize a change in the spatial location of a familiar object. Movement of an object causes normal mice to preferentially explore that object (rather than other familiar objects that remain in the same place). But the GABA_AR mutant mice appeared not to recognize the displacement of an object and explored displaced and nondisplaced objects equally. The authors point out that, although we know well that modulation of these receptors by drugs can alter behavior, less information is available on how normal modulation of the receptors in response to neuronal signals does so. Their results show that receptor trafficking controlled by phosphorylation is a key component of a learned behavior in the mouse.

V. Tretter, R. Revilla-Sanchez, C. Houston, M. Terunuma, R. Havekes, C. Florian, R. Jurd, M. Vithlani, G. Michels, A. Couve, W. Sieghart, N. Brandon, T. Abel, T. G. Smart, S. J. Moss, Deficits in spatial memory correlate with modified -aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 106, 20039–20044 (2009). [Abstract] [Full Text]