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Free keywords:
Mouse; Gria1; GluR1; GluR−A; PDZ; AMPA receptors; Porsolt swim test; Behavioral despair; Depression
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