Get access

A role for alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid GluR1 phosphorylation in the modulatory effects of appetitive reward cues on goal-directed behavior

Authors

  • Hans S. Crombag,

    1. Department of Psychological & Brain Sciences, Neurogenetics and Behavior Center, The Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
    • *

      Present address: Department of Psychology, School of Life Sciences, The University of Sussex, Johns Maynard Smith Building Room 5D9, Brighton, East Sussex, UK

  • Jeffrey M. Sutton,

    1. Department of Psychological & Brain Sciences, Neurogenetics and Behavior Center, The Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • Kogo Takamiya,

    1. The Howard Hughes Medical Institute, Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • Peter C. Holland,

    1. Department of Psychological & Brain Sciences, Neurogenetics and Behavior Center, The Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • Michela Gallagher,

    1. Department of Psychological & Brain Sciences, Neurogenetics and Behavior Center, The Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • Richard L. Huganir

    1. The Howard Hughes Medical Institute, Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author

Dr H. S. Crombag, *present address below.
E-mail: H.Crombag@sussex.ac.uk

Abstract

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor regulation has been shown to be critically involved in synaptic plasticity underlying learning and memory. This regulation occurs through trafficking of the receptor and modulation of the receptor’s channel properties, both of which depend on protein phosphorylation. Using homologous recombination (knock-in) techniques we targeted two phosphorylation sites on the AMPA-GluR1 receptor: the Ser831 site, phosphorylated by calcium calmodulin-dependent protein kinase II/protein kinase C, and the Ser845 site, phosphorylated by protein kinase A. Mice with mutations that prevented phosphorylation at one or both of these sites were tested on a single-outcome Pavlovian-instrumental transfer task often used to assess the acquisition of incentive motivation by cues for food reinforcement. Mice were separately trained to associate a Pavlovian cue with food and to perform an instrumental lever-press response to earn that same reward. During a transfer test, the cue was presented while the mice were lever-pressing under extinction conditions. Whereas wild-type control mice showed substantial enhancement of lever-pressing when the cue was presented (i.e. showed Pavlovian-instrumental transfer), mice with mutations at both of these phosphorylation sites showed no evidence of such transfer. By contrast, mice with either serine site mutated alone showed normal transfer. These results suggest critical roles for GluR1 phosphorylation pathways in a form of incentive learning that can play an important part in regulating normal motivated behavior as well as maladaptive behaviors such as addiction and eating disorders.

Ancillary