Rapid and sustained restoration of astrocytic functions by ketamine in depression model mice

Molecules with fast-acting antidepressant effects have potentials to become new antidepressants. Here we report the fast-acting (1hr) antidepressant effects of ketamine (10 mg/kg, i.p.) in chronic adreno-cortico-tropic-hormone (ACTH)-induced and chronic unpredictable mild stress (CUMS)-induced depression mouse models. These behavioral anti-depressant effects are associated with normalized expression of glutamate transporter-1(GLT-1), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and eukaryotic elongation factor 2 phosphorylation (p-eEF2) in the prelimbic prefrontal cortex (PrL-PFC). Excitatory neurons in PrL also showed reduced ambient glutamate responses to synaptic stimulation, and reduced ambient NMDA receptor responses after ketamine injection. Interestingly, ketamine induced biochemical and electrophysiological changes still occurred with GLT-1 knockdown in PrL, suggesting that elevated GLT-1 level is not required for ketamine to exert its antidepressant effect. At the same time, ketamine did not elevate GLT-1 level in the isolated astrocytes, suggesting distinct contributions from neurons and astrocytes to ketamine-induced changes.