A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression.

The N-methyl-D-aspartate receptor (NMDA-R) antagonist S-ketamine has been approved as a rapid-acting antidepressant for treatment-resistant depression (TRD). The antidepressant mechanisms have not fully been elucidated; however, alterations of synaptic proteins and mechanisms may play a vital role. Here, we study the effect of a single subanaesthetic dose of 15 mg/kg S-ketamine vs saline 1 h after administration in the Wistar Kyoto rat model of depression on the density of synaptic vesicle glycoprotein 2A (SV2A) and the metabotropic glutamate receptor 5 (mGluR5) using [H]UCB-J and [H]MPEPγ autoradiography, respectively, compared with control Wistar Hannover rats. In a separate cohort of Wistar Kyoto rats, we investigate the transcriptional regulation of presynaptic markers , , postsynaptic markers , NMDA receptor subunits , AMPA receptor subunits , GABA type A receptor-associated protein (), glutamate metabotropic receptor subtype 5 (), and brain-derived neurotrophic factor () using real-time quantitative polymerase chain reaction (qPCR) in hippocampus in response to S-ketamine vs saline injection. In Wistar Kyoto rats, S-ketamine increases [H]UCB-J binding to SV2A compared to saline-injected controls in the nucleus accumbens and dorsal and ventral hippocampus, an effect absent in the Wistar Hannover strain. No changes were observed in [H]MPEPγ binding to mGluR5, nor in gene regulation. S-ketamine can regulate presynaptic SV2A density in brain areas relevant to depression in the Wistar Kyoto model, but not in controls, suggesting a role for SV2A in the antidepressant effects of S-ketamine.