Research Article: Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission

Date Published: March 13, 2019

Publisher: Public Library of Science

Author(s): Gyorgy Lur, Mona Fariborzi, Michael J. Higley, Michelle M. Adams.


A growing body of literature has demonstrated the potential for ketamine in the treatment of major depression. Sub-anesthetic doses produce rapid and sustained changes in depressive behavior, both in patients and rodent models, associated with reorganization of glutamatergic synapses in the prefrontal cortex (PFC). While ketamine is known to regulate N-methyl-D-aspartate (NMDA) -type glutamate receptors (NMDARs), the full complement of downstream cellular consequences for ketamine administration are not well understood. Here, we combine electrophysiology with 2-photon imaging and glutamate uncaging in acute slices of mouse PFC to further examine how ketamine alters glutamatergic synaptic transmission. We find that four hours after ketamine treatment, glutamatergic synapses themselves are not significantly affected. However, levels of the neuromodulatory Regulator of G-protein Signaling (RGS4) are dramatically reduced. This loss of RGS4 activity is associated with disruption of the normal compartmentalization of synaptic neuromodulation. Thus, under control conditions, α2 adrenergic receptors and type B γ-aminobutyric acid (GABAB) receptors selectively inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -type glutamate receptors (AMPARs) and NMDARs, respectively. After ketamine administration and reduction in RGS4 activity, this selectivity is lost, with both modulatory systems broadly inhibiting glutamatergic transmission. These results suggest a novel mechanism by which ketamine may influence synaptic signaling and provide new avenues for the exploration of therapeutics directed at treating neuropsychiatric disorders, such as depression.

Partial Text

Major depression, with a lifetime prevalence of 17%, presents a significant psychological and economical burden for both individuals and society [1, 2]. Despite enormous efforts to develop effective treatments, available therapeutic interventions have considerable limitations. For example, most antidepressant medications take several weeks to achieve maximal benefit and a significant fraction of patients remain refractory to treatment [3, 4]. However, recent studies in both clinical and basic science fields have demonstrated promising results using low doses of the drug ketamine. Indeed, sub-anesthetic doses of ketamine produce rapid antidepressant actions within a few hours [5–7], even in otherwise refractory patients [8]. Thus, the potential benefits of this new pharmacological intervention provide great promise for the treatment of major depression.

In our present study, we demonstrate significant dysregulation of neuromodulatory control over glutamatergic signaling in the mouse prefrontal cortex following the administration of a single, sub-anesthetic dose of ketamine. Specifically, following ketamine administration, adrenergic and GABAergic receptor activation inhibits NMDARs and AMPARs, respectively, a phenomenon that does not occur in untreated animals. Our results suggest this process may be mediated by acute reduction in levels of the small GTPase RGS4, which were previously shown to prevent neuromodulatory cross-talk in dendritic spines [26]. Our findings thus extend our knowledge of targets for ketamine that may contribute to or interact with its antidepressant actions in vivo.




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