Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
541—Mood Disorders: Animal Models II
Tuesday, November 12, 2013, 8:00 am - 12:00 noon
541.17: Implications of NMDAR GluN2B subunits within the BNST in the antidepressant effects of ketamine
Location: Halls B-H
*K. LOUDERBACK1,2,3,4, B. D. TURNER2, T. L. FETTERLY2, D. G. WINDER1,3,2,4; 1Mol. Physiol. and Biophysics, 2Brain Inst., 3Neurosci. Program in Substance Abuse, 4Kennedy Ctr., Vanderbilt Univ., Nashville, TN
Abstract Body: Low-dose ketamine induces rapid and long-lasting antidepressant effects in humans, and this effect has been replicated in rodent models of depression. The mechanisms of this antidepressant effect are not fully understood. Ketamine acts as a noncompetitive N-methyl D-aspartate receptor (NMDAR) antagonist, and studies have demonstrated that the ifenprodil derivative Ro 25-6981 (Ro), which inhibits GluN2B-containing NMDARs, is also capable of reducing depression-like behaviors in rodents. However, recent studies have shown that ifenprodil derivatives have a number of off-target effects at other sites critical for affective disorders, including the norepinephrine and serotonin transporters. Further, systemic administration of compounds such as ketamine and Ro does not allow determination of circuitry crucial for their actions. The GluN2B subunit is highly expressed in the bed nucleus of the stria terminalis (BNST), where it plays an important role in long-term potentiation (LTP). Given multiple studies implicating the BNST in negative affective disorders, we sought to explore the role of the GluN2B subunit within the BNST on affective behavior. First, we demonstrate that systemic ketamine (3mg/kg) and Ro (5mg/kg) decrease latency to feed in the Novelty-Induced Feeding Suppression (NIFS) behavioral paradigm following acute restraint stress. Interestingly, under similar conditions we did not find significant effects of either drug in the elevated zero maze (EZM) or forced swim test (FST). We next utilized a combination of floxed GluN2B mice and stereotaxic delivery of lentiviral Cre-recombinase to delete the grin2b gene specifically from the BNST (BNSTGluN2BKO). Similar to ketamine- and Ro-treated wild type mice, BNSTGluN2BKO mice have significantly reduced latency to feed in the NIFS paradigm but do not show alterations in the EZM or the FST. This effect was specific to GluN2B, as no effect was observed with similar LV-CRE injections into a homozygous floxed glucocorticoid receptor mouse BNST. To determine the effects of BNST GluN2B deletion or systemic ketamine administration on plasticity within the BNST, we examined field potential induction of LTP in the BNST. We found that in BNSTGluN2BKO mice, an early component of LTP was enhanced compared to control virus (lentiviral GFP) injected mice. We have previously demonstrated that LTP in BNST is disrupted by prior stress. We are currently examining the impact of NMDAR inhibition and deletion on this disruption. In total, these data suggest that GluN2B containing NMDARs in the BNST play an important role in modulation of affective behavior.
Lay Language Summary: In this study, we have uncovered a key brain region involved in the fast-acting antidepressant actions of ketamine. Major depression is a serious and highly prevalent psychiatric illness, with over 120 million estimated sufferers worldwide and 5% of the United States population reporting a depressive episode every year. Although treatments are available, typical antidepressants (most commonly selective serotonin reuptake inhibitors, or SSRIs) require daily administration and take weeks to begin to work. Additionally, many patients are resistant to available treatments. Hope for more rapid and successful treatment of depression arose around twenty years ago when researchers found that a single low dose of ketamine was able to improve depression symptoms in patients with major depression within three hours, and this effect was maintained for weeks. In this study, we provide evidence that antidepressant actions of ketamine may occur via inhibition of specific N-methyl D-aspartate (NMDA) receptors in a brain region called the bed nucleus of the stria terminalis (BNST). Ketamine acts in the brain to inhibit the NMDA receptor, which is comprised of four subunits (in several different combinations) and binds the excitatory neurotransmitter glutamate. However, it remains unclear what type of NMDA receptor subunit ketamine works through and where in the brain these antidepressant actions are occurring. Antidepressant actions of drugs can be studied in animals to gain understanding of mechanisms they work through. Mice are cautious creatures, such that the availability of a highly palatable food in an environment unpleasant to the mouse (brightly lit, novel environment) generates a conflict that delays the mouse’s consumption of the food. The length of time (latency) it takes for a mouse to first consume the palatable substance (Ensure) in the novel environment is a measure of its emotional state. Previous studies have demonstrated that ketamine administration decreases this latency. We observed a decrease in this latency both with ketamine treatment as well as with another drug that inhibits a particular subunit of the NMDA receptor, the GluN2B subunit. Unfortunately, this drug has other targets related to depression behavior. Further, administration of these drugs throughout the body does not allow identification of the specific brain regions involved in the antidepressant outcomes. In order to determine where in the brain ketamine is acting and if it really is acting through the GluN2B subunit, we used a genetic strategy that allowed us to decrease the expression of the gene that encodes the GluN2B subunit. We did this in a specific brain region of interest, the bed nucleus of the stria terminalis, or BNST. The BNST is a small region that contains high levels of NMDA receptor subunit GluN2B, connects with other brain regions important for stress and reward behaviors, and is involved in behaviors related to anxiety, addiction, and, as shown in recent studies, depression. After we decreased the GluN2B subunit of the NMDA receptor from the BNST in mice, we administered the same task described above, again examining latency to drink Ensure. We found that these mice exhibited a decreased latency, very similar to mice treated with ketamine. These results indicate that ketamine’s antidepressant effects at least in part involve blockade of NMDA receptors containing the GluN2B subunit in the BNST. Understanding how and where the long-lasting antidepressant effects of ketamine are occurring could provide key insights that will improve treatment for millions of depression sufferers for whom typical treatments are not effective.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit