Glia and glutamate: new key players in the pathology of major depression
Postmortem studies in depression reveal age-dependent cell pathology in prefrontal cortex. Prominent reductions in glia and specifi cally, in astrocytes, are observed in younger depressed, whereas neuronal pathology is found in elderly with depression. As astrocytes regulate extracellular concentrations of glutamate (via glial glutamate transporters), an early defi cit in astrocytes could lead to increases in extracellular glutamate and toxic damage to neurons as depression progresses. This is supported by postmortem studies of reduced expression of mRNA and protein for the glial glutamate transporter in younger depressed and by reductions in glutamatergic neurons in elderly depressed. Moreover, alterations in glutamate metabolism are reported in neuroimaging studies of depressed patients. Interestingly, agents increasing expression of glial glutamate transporters and/or altering glutamate neurotransmission show antidepressant activity. Our hypothesis that glial pathology is an initial stage of cellular and neurochemical changes in depression was confi rmed by observations of glial/glutamate defi cits in chronically stressed rodents. Pharmacologically-induced loss of astroglia, but not neurons in the rat prefrontal cortex will induce depressive-like behaviors. Moreover, treatment with riluzole (a modulator of glutamate release) reverses stress-induced depressive-like behaviors and blocks glia impairments providing a link between dysfunction of glia and glutamate in depression.