Astrocytic Contribution to the Glutamatergic Transmission in Schizophrenia

Schizophrenia is a chronic mental disorder encompassing an array of cognitive and behavioral manifestations. Although the disease molecular pathophysiology remains essentially unknown, evidence exists for abnormalities within all the main neurotransmitter systems and various cortical and subcortical brain structures, albeit with no unifying/overarching hypothesis connecting the existent knowledge. Moreover, no current animal model or biological construct reproduces the complexity of the disease with acceptable validity. In my work I have taken a multidisciplinary approach to study the live and postmortem human brains of people with schizophrenia, focusing specifically on the glutamatergic abnormalities in the hippocampus, one brain region repeatedly found to bear structural, molecular, and blood flow abnormalities in the disease. I have started with the in vivo measurement of glutamate and glutamine using magnetic resonance spectroscopy, thus getting a “high-level” sense of the glutamatergic transmission changes in the hippocampi of subjects with schizophrenia. Concretely, I have found that untreated people with schizophrenia have reduced levels of glutamate compared to their healthy counterparts, but this reduction can be partially reversed by antipsychotic medication. To allow for a more “small-scale” characterization of the glutamatergic transmission impairments, I have used postmortem brain tissue to zoom in on the glutamatergic synapse, viewed as a “tripartite synapse”. Apart from the pre- and postsynaptic neurons, the third component is represented by the astrocyte, the brain glial cell that is responsible for most of the glutamate recycling and that attunes the glutamatergic synapse to the overall energetic metabolism of the brain. I have found that glutamate recycling is impaired in schizophrenia, selectively in the dentate gyrus, one of vii the hippocampal subregions, and the specific abnormalities reside in the glutamate transporters, responsible clearing up synaptic glutamate.