title: Does conventional anti-bipolar and antidepressant drug therapy reduce NMDA-mediated neuronal excitation by downregulating astrocytic GluK2 function?
abstract: 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, Ca(2+)-dependent ERK(1/2) phosphorylation in the astrocytes. Chronic treatment with the SSRI fluoxetine enhances astrocytic GluK2 expression, but increases mRNA editing, abolishing glutamate-mediated ERK(1/2) phosphorylation and [Ca(2+)](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 IP(3) 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 Ca(2+)-dependent K(+) flux. This may be secondary to the induced astrocytic [Ca(2+)](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.
authors.affiliation: Department of Clinical Pharmacology, China Medical University, Shenyang, PR China. hkkid08@yahoo.com
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Du
authors.forename: Fanli
authors.initials: F
authors.lastname: Wang
authors.forename: Leif
authors.initials: L
authors.lastname: Hertz
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001714:Bipolar Disorder / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D016202:N-Methylaspartate / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018092:Kainic Acid Receptors / Q000502:physiology*; D000097806:GluK2 Kainate Receptor
chemical_list: D000928:Antidepressive Agents; D016202:N-Methylaspartate; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor