Does conventional anti-bipolar and antidepressant drug therapy reduce NMDA-mediated neuronal excitation by downregulating astrocytic GluK2 function?

Chronic treatment with anti-bipolar drugs (lithium, carbamazepine, and valproic acid) down-regulates mRNA and protein expression of kainate receptor GluK2 in mouse brain and cultured astrocytes. It also abolishes glutamate-mediated, Ca2+-dependent ERK1/2 phosphorylation in the astrocytes. Chronic treatment with the SSRI fluoxetine enhances astrocytic GluK2 expression, but increases mRNA editing, abolishing glutamate-mediated ERK1/2 phosphorylation and [Ca2+]i increase, which are shown to be GluK2-mediated. Neither drug group affects Glu4/Glu5 expression necessary for GluK2's ionotropic effect. Consistent with a metabotropic effect, the PKC inhibitor GF 109203X and the IP3 inhibitor xestospongin C abolish glutamate stimulation in cultured astrocytes. In CA1/CA3 pyramidal cells in hippocampal slices, activation of extrasynaptic GluK2 receptors, presumably including astrocytic, metabotropic GluK2 receptors, causes long-lasting inhibition of slow neuronal afterhyperpolarization mediated by Ca2+-dependent K+ flux. This may be secondary to the induced astrocytic [Ca2+]i increase, causing release of ‘gliotransmitter’ glutamate. Neuronal NMDA receptors respond to astrocytic glutamate release with enhancement of excitatory glutamatergic activity. Since reduction of NMDA receptor activity is known to have antidepressant effect in bipolar depression and major depression, these observations suggest that the inactivation of astrocytic GluK2 activity by antidepressant/anti-bipolar therapy ameliorates depression by inhibiting astrocytic glutamate release. A resultant strengthening of neuronal afterhyperpolarization may cause reduced NMDA-mediated activity.

► In astrocytes chronic anti-bipolar drug treatment reduces expression of GluK2.
► Chronic antidepressant drug treatment increases GluK2 expression and editing.
► GluK2 editing or reduced GluK2 expression inhibit increase in [Ca2+]i by glutamate.
► Released glutamate acts on neuronal receptors to promote synaptic activity.
► Reduced NMDA activity after inhibited astrocytic Ca2+ response is anti-depressant.