Selective siRNA-mediated suppression of astroglial glutamate transporters in infralimbic cortex induces depressive-like behaviors in mice

Abstract

Major depression has been associated with alterations of the monoaminergic systems. Emerging evidences suggest that dysregulations of glutamatergic neurotransmission in the prefrontal cortex (PFC) are involved in the pathophysiology of depression. Notably, astrocytes regulate excitatory neurotransmission by removing synaptic glutamate via the glutamate transporters GLAST and GLT-1. We hypothesized that reduced expression of GLAST and GLT-1 in the infralimbic PFC would induce depressive-like behaviors in mice due to disabled glutamate reuptake. We microinjected small interfering RNA molecules targeting GLAST or GLT-1 (GLAST-siRNA or GLT-1-siRNA, respectively) unilaterally into prelimbic (PrL) or infralimbic (IL) cortices of C57BL/6J mice and examined the cellular and behavioral effects. Local GLAST-siRNA microinfusion in the mouse IL cortex (60 ¿g/¿l ¿ 4.2 nmol) reduced selectively GLAST mRNA and protein levels to ~80% of control mice 24h post-administration. GLAST knockdown mice exhibited depressive-like behaviors including anhedonia as well as increased immobility time in the TST (125% of controls) and FST (128% of controls). Likewise, intra-IL cortex infusion of GLT-1-siRNA (60 ¿g/¿l ¿ 4.2 nmol) reduced GLT-1 expression (~70% of controls) and mice showed increased immobility time in TST (130% of controls) and FST (118% of controls) as well as decreased sucrose preference. However, microinfusion of GLAST-siRNA or GLT-1-siRNA in the PrL cortex did not affect behavioral responses in both behavioral tests despite the reductions of GLAST and GLUT-1 mRNA were similar to those achieved in the IL cortex. Overall, these findings improve our understanding of the pathophysiology of major depression, and help to identify novel targets in antidepressant drug development.