title: GluA1 and its PDZ-interaction: a role in experience-dependent behavioral plasticity in the forced swim test.
abstract: Glutamate receptor dependent synaptic plasticity plays an important role in the pathophysiology of depression. Hippocampal samples from clinically depressed patients display reduced mRNA levels for GluA1, a major subunit of AMPA receptors. Moreover, activation and synaptic incorporation of GluA1-containing AMPA receptors are required for the antidepressant-like effects of NMDA receptor antagonists. These findings argue that GluA1-dependent synaptic plasticity might be critically involved in the expression of depression. Using an animal model of depression, we demonstrate that global or hippocampus-selective deletion of GluA1 impairs expression of experience-dependent behavioral despair. This impairment is mediated by the interaction of GluA1 with PDZ-binding domain proteins, as deletion of the C-terminal leucine alone is sufficient to replicate the behavioral phenotype. Our results provide evidence for a significant role of hippocampal GluA1-containing AMPA receptors and their PDZ-interaction in experience-dependent expression of behavioral despair and link mechanisms of hippocampal synaptic plasticity with behavioral expression of depression.
authors.affiliation: Laboratory of Neural Circuits and Plasticity, University of Southern California, 3641 Watt Way, Los Angeles, CA-90089, USA. ffreuden@gmail.com
authors.forename: Florian
authors.initials: F
authors.lastname: Freudenberg
authors.forename: Verena
authors.initials: V
authors.lastname: Marx
authors.forename: Volker
authors.initials: V
authors.lastname: Mack
authors.forename: Liliana E
authors.initials: LE
authors.lastname: Layer
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Tansu
authors.initials: T
authors.lastname: Celikel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D006380:Helplessness, Learned; D006624:Hippocampus / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D054731:PDZ Domains / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism; D013550:Swimming
chemical_list: D018091:Receptors, AMPA