Abstract
The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine - an NMDA receptor (NMDAR) antagonist – has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.
Highlights
Drugs currently used for the treatment of major depression target monoaminergic neurotransmission, primarily serotonin and noradrenaline pathways, such as the selective serotonin and noradrenaline reuptake inhibitors
In the present study we have analyzed the role of NMDARdependent neurotransmission in GABAergic PV interneurons for the acute antidepressant properties of NMDA receptor (NMDAR) antagonists as well as for the regulation of depression-like behavior
A possible mechanism for the antidepressant properties of NMDAR antagonists is the disinhibition of glutamatergic neurons of the medial prefrontal cortex, through a decrease in the activity of PV fast-spiking interneurons [32]
Summary
Drugs currently used for the treatment of major depression target monoaminergic neurotransmission, primarily serotonin and noradrenaline pathways, such as the selective serotonin and noradrenaline reuptake inhibitors. Antidepressant-like effects after acute NMDA receptor (NMDAR) antagonist treatment have been observed in many models of depression, including inescapable stress, the forced swimming test, the tail suspension test, learned helplessness models of depression, and exposure to chronic mild stress procedures [3], [7,8,9]. This suggests that glutamate NMDAR antagonist-based treatments might represent an effective alternative to current therapies to treat depression [10,11]
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