Impaired glutamate reuptake induces synaptic mistuning in rat hippocampal slices, that can be counteracted by ketamine

Mistuning of synaptic transmission has been proposed to underlie many psychiatric disorders, with decreased reuptake of the excitatory neurotransmitter glutamate as one contributing factor. Synaptic tuning occurs through several diverging and converging forms of plasticity. By recording evoked field postsynaptic potentials in the CA1 area in hippocampal slices, we found that inhibiting glutamate transporters using DL-TBOA causes retuning of synaptic transmission, resulting in a new steady state with reduced synaptic strength and a lower threshold for inducing long-term synaptic potentiation (LTP). Moreover, we also found reduced threshold for LTP in a rat model of depression that has decreased levels of glutamate transporters. Most importantly, we found that the antidepressant ketamine counteracts the effects of increased glutamate on the various steps involved in synaptic retuning. We therefore propose that ketamine’s mechanism of action as an antidepressant is to restore adequate synaptic tuning.