Murine model of depression: astroglial glutamate transporter knockdown in infralimbic cortex induces a depressive phenotype

Trabajo presentado en el Neuroscience 2017, celebrado en Washington del 11 al 15 de noviembre de 2017Emerging evidence suggests that dysregulations of glutamatergic neurotransmission in prefrontal cortex are involved in the pathophysiology of depression. Astrocytes regulate excitatory neurotransmission by removing synaptic glutamate via GLAST and GLT-1 transporters. We demonstrated that unilateral knockdown of GLAST and GLT-1 in mouse infralimbic (IL) cortex induced by the local micro-infusion of small interfering RNAs (siRNA) targeting either transporter evoked a depressive-like phenotype. Conversely, intra-prelimbic (Prl) cortex microinfusion of both siRNAs did not affect behavioral responses despite comparable reductions of GLAST and GLT-1-1 expression in both PFC subdivisions. Downregulation of GLAST and GLT-1 remained diminished for at least 3 day and recovered 7 days post-administration. The depressive-like phenotype induced by reducing GLT-1 and GLAST expression in IL may be due to a hypoactive serotonergic (5-HT) system since it was reversed by the antidepressant drug citalopram. Likewise, microdialysis experiments revealed that siRNA-treated mice exhibited a reduced basal 5-HT release in the dorsal raphe nucleus (DRN) compared with controls, and a similar effect of veratridine in both experimental groups, indicating a similar intracellular 5-HT content. Further, local infusion of the GABAA receptor antagonist bicuculline increased DRN-5-HT release more markedly in siRNA-treated mice, suggesting a greater inhibition of 5-HT neurons via GABAA receptors. However, local downregulation of both transporters in PrL did not alter baseline 5-HT in DRN not the effect of bicuculline on 5-HT release. Taken together, these observations suggest that 1) an alteration of astroglial glutamate uptake in ventral PFC regions (IL) evokes downstream changes in 5-HT function, associated to a depressive-like phenotype in mice, and 2) the regional specificity of the effect suggests a differential functional connectivity between PrL/IL and DRN 5-HT neurons. In addition, this potential new model of MDD shows several physio pathological markers observed in patients: reduced expression of GFAP, a smaller number of astrocytes in mPFC, as well as a decreased BDNF expression in mPFC and the hippocampal formation, which is highly and significantly correlated with the degree of glutamate transporter knockdown in IL, indicating a direct relationship between both processes. Overall, these findings improve our understanding of the pathophysiology of depression and could help to identify novel targets in antidepressant drug development, since this potential new MDD model mimics many of the functional and molecular alterations observed in MDD patients.Peer reviewe