A Role for Astrocytes in Dopamine-Glutamate Interactions of the Prefrontal Cortex

Abstract

Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Evidence has demonstrated that manipulation of either neurotransmitter can lead to alterations in the other. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for >90% of cortical glutamate uptake. The effect of dopamine denervation on glutamate transporters, and other glutamate-related proteins in the prefrontal cortex (PFC) , is unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters and glutamate-related proteins. PFC dopamine denervation elicited a marked increase in GLT-1 and mGluR2/3 protein levels, but had no effect on levels of other glutamate transporters or glutamate-related proteins. Increases in GLT-1 and mGluR2/3 were dependent on the extent of dopamine depletion with “moderate” depletion resulting in increased protein levels, while “severe” dopamine depletion failed to elicit an increase in GLT-1 or mGluR2/3. Astrocyte number and activation were not affected by dopamine depletion. High affinity glutamate transport was positively correlated with the extent of dopamine depletion. Increases in GLT-1 and mGluR2/3 may act to homeostatically regulate increases in extracellular glutamate levels and attenuate symptoms associated with prefrontal cortical dysfunction in disorders such as schizophrenia.