Abstract
The causes of major depression remain unknown. Antidepressants elevate monoamine concentrations, particularly serotonin, but it remains uncertain which downstream events are critical to their therapeutic effects. We report that endogenous serotonin selectively potentiated excitatory synapses formed by the temporoammonic (TA) pathway with CA1 pyramidal cells via activation of 5-HT1BRs, without affecting nearby Schaffer collateral synapses. This potentiation was expressed postsynaptically by AMPA-type glutamate receptors and required calmodulin-dependent protein kinase-mediated phosphorylation of GluA1 subunits. Because they share common expression mechanisms, long-term potentiation and serotonin-induced potentiation occluded each other. Long-term consolidation of spatial learning, a function of TA-CA1 synapses, was enhanced by 5-HT1BR antagonists. Serotonin-induced potentiation was quantitatively and qualitatively altered in a rat model of depression, restored by chronic antidepressants, and required for the ability of chronic antidepressants to reverse stress-induced anhedonia. Changes in serotonin-mediated potentiation, and its recovery by antidepressants, implicate excitatory synapses as a locus of plasticity in depression.
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