Regionally selective knockdown of astroglial glutamate transporters in infralimbic cortex induces a depressive phenotype in mice

Abstract

Elevation of energy metabolism and disturbance of astrocyte number/function in the ventral anterior cingulate cortex (vACC) contributes to the pathophysiology of major depressive disorder (MDD). Functional hyperactivity of vACC may result from reduced astrocytic glutamate uptake and increased neuronal excitation. Here we tested this hypothesis by knocking‐down astrocytic glutamate transporter GLAST/GLT‐1 expression in mouse infralimbic (IL, rodent equivalent of vACC) or prelimbic (PrL) cortices using RNAi strategies. Unilateral siRNA (small interfering RNA) microinfusion targeting GLAST or GLT‐1 in mouse IL induced a moderate (20–30%) and long‐lasting (7 days) decrease in their expression. Intra‐IL GLAST‐/GLT‐1 siRNA microinfusion reduced the number of glial fibrillary acidic protein (GFAP)‐positive and glutamine synthetase (GS)‐positive astrocytes and evoked a depressive‐like phenotype reversed by citalopram and ketamine. Intra‐IL GLAST or GLT‐1 knockdown markedly reduced serotonin (5‐HT) release in the dorsal raphe nucleus (DR) and induced an overall reduction of brain‐derived neurotrophic factor (BDNF) expression in ipsilateral and contralateral hemispheres. Egr‐1 (early growth response protein‐1) labeling suggests that both siRNAs enhance the GABAergic tone onto DR 5‐HT neurons, leading to an overall decrease of 5‐HT function, likely related to the widespread reduction on BDNF expression. Conversely, similar reductions of GLAST and GLT‐1 expression in PrL did not induce a depressive‐like phenotype. These results suggest that a focal glial change in IL translates into global change of brain activity by virtue of the descending projections from IL to DR and the subsequent attenuation of serotonergic function in forebrain, an effect perhaps related to the varied symptomatology of MDD.

Brain NMDA Receptors in Schizophrenia and Depression

“…Indeed, a reduced number and volume of astrocytes was found in the prefrontal cortex [ 219 ] and the hippocampus [ 220 ], in the chronic unpredictable stress procedure and chronic social defeat stress paradigm. Interestingly, neurotoxic lesioning of astrocytes in the prefrontal cortex is sufficient to induce depressive-like behaviors in rodents [ 221 ], an effect also found after knocking-down the expression of astrocytic glutamate transporter GLAST/GLT-1 in the prefrontal cortex of the mouse, using small interfering RNA (siRNA) strategies [ 222 ].…”

A Focus on the Functions of Area 25

“…Acute versus more sustained activation of IL may contribute to the variation in the results, with acute effects tending to be anxiogenic whilst prolonged effects are more likely anxiolytic. However, very recently, sustained activation induced by genetic knockdown of the astrocytic glutamate transporter GLAST/GLT-1 expression, induced a depressive-like phenotype on the tail suspension and forced swim tests [169]. Other contributory factors to the variation in findings may therefore include whether the animal was tested in its subjective ‘night’ or ‘day’, with the former being likely to enhance the level of stress experienced; however, this information is not always provided.…”

“…It should be noted however that in the latter [173], cannulas passed through the PL to reach the IL, but infusions were not compared with equivalent manipulations of the PL. Nevertheless, additional support of a pro-depressant effect of IL activation in the reward domain, sustained activation by knockdown of GLAST/GLT-1 expression reduced sucrose consumption, an effect that was not due to PL involvement [169]. Moreover, IL activation using the GABA antagonist bicuculline dampens the intense eating behavior generated by glutamate disruptions in the nucleus accumbens shell [174].…”

Neuron-to-microglia Crosstalk in Psychiatric Disorders

“…Fullana et al . found that in mice, selective knockdown of astrocyte glutamate uptake results in a depressive-like phenotype due to serotonergic hypoactivity in the infralimbic cortex area [ 8 ]. There are also many astrocyte-related studies in which antidepressants affect various neurotransmitters, i.e ., serotonin, glutamate, energy homeostasis, and the regulation of blood-brain barrier integrity by astrocytes [ 9 ].…”