GluA1 and its PDZ-interaction: A role in experience-dependent behavioral plasticity in the forced swim test

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.

► Experience-dependent expression of behavioral despair is GluA1-dependent.
► Hippocampus-specific removal of GluA1 impairs expression of behavioral despair.
► GluA1 PDZ-interaction is required for the expression of behavioral despair.