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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. [Copyright &y& Elsevier]

Abstract: Expression, functional properties, and clustering of α1-, α2-, and α3-subunit containing GABAA receptors (GABAARs) were studied in dorsomedial SON neurons of the adult female rat supraoptic nucleus (SON) around parturition. We show that, although the decay time constant (τdecay) of GABAergic postsynaptic currents between and within individual recordings was very diverse, ranging from fast (i.e., α1-like) to significantly slower (i.e., non-α1-like), there was an overall shift towards slower decaying synaptic currents during the onset of lactation. This shift is not due to changes in mRNA expression levels, because real-time quantitative PCR assays indicated that the relative contribution of α1, α2, and α3 remained the same before and after parturition. Also, changes in phosphorylation levels are not likely to affect the τdecay of postsynaptic currents. In α-latrotoxin (α-LTX)-induced bursts of synaptic currents from individual synapses, the τdecay of consecutive synaptic events within bursts was very similar, but between bursts there were large differences in τdecay. This suggested that different synapses within individual SON neurons contain distinct GABAAR subtypes. Using multilabeling confocal microscopy, we examined the distribution of postsynaptic α1-, α2-, and α3-GABAARs, based on colocalization with gephyrin. We show that the three GABAAR subtypes occurred either in segregated clusters of one subtype as well as in mixed clusters of two or possibly even three receptor subtypes. After parturition, the density and proportion of clusters containing α2- (or α3-), but not α1-GABAARs, was significantly increased. Thus, the functional synaptic diversity at the postsynaptic level in dorsomedial SON neurons is correlated with a differential clustering of distinct GABAAR subtypes at individual synapses. [Copyright &y& Elsevier]