Endoplasmic reticulum stress protein GRP78 for ketamine's antidepressant effects

Ketamine is a fast-acting, long-lasting novel antidepressant. However, underpinning intracellular mechanisms remain unclear. We conducted an unbiased screening for genes that were less expressed in the prefrontal cortex (PFC) of mice that did not display antidepression-like effects to ketamine. GO analysis implicated endoplasmic reticulum and protein folding; in particular, GRP78, a stress-induced chaperone protein critical for protein folding, was reduced. We showed that GRP78 deficiency in PFC neurons induced depressive-like behaviors, whereas its overexpression produced anti-depression-like effects, revealing a novel function of GRP78. Prefrontal GRP78 was necessary for ketamines antidepressant-like effects. GRP78 was also required for ketamine to increase calcium activity and glutamatergic transmission. Enhancing GRP78 by viral infection and azoramide enabled non-responsive mice to respond to ketamine. Together, our results demonstrate that GRP78 is critical for ketamine to execute antidepressant effects by potentiating glutamatergic transmission in the PFC. HighlightsO_LIGRP78 was identified in non-biased screens for proteins that were lower in the PFC of mice that failed to exhibit antidepression-like effects after ketamine. C_LIO_LIReducing GRP78 in the PFC induced depressive-like behaviors while increasing GRP78 had opposite effects in wildtype mice. C_LIO_LIGRP78 is required for ketamine to increase calcium activity in excitatory neurons and glutamatergic transmission. C_LIO_LIEnhancing GRP78 by viral infection and by azoramide enabled non-responsive mice to respond to ketamine. C_LI