Abstract
The behavioral response to antidepressants is closely associated with physiological changes in the function of neurons in the hippocampal dentate gyrus (DG). Parvalbumin interneurons are a major class of GABAergic neurons, essential for DG function, and are involved in the pathophysiology of several neuropsychiatric disorders. However, little is known about the role(s) of these neurons in major depressive disorder or in mediating the delayed behavioral response to antidepressants. Here we show, in mice, that hippocampal parvalbumin interneurons express functionally silent serotonin 5A receptors, which translocate to the cell membrane and become active upon chronic, but not acute, treatment with a selective serotonin reuptake inhibitor (SSRI). Activation of these serotonergic receptors in these neurons initiates a signaling cascade through which Gi-protein reduces cAMP levels and attenuates protein kinase A and protein phosphatase 2A activities. This results in increased phosphorylation and inhibition of Kv3.1β channels, and thereby reduces the firing of the parvalbumin neurons. Through the loss of this signaling pathway in these neurons, conditional deletion of the serotonin 5A receptor leads to the loss of the physiological and behavioral responses to chronic antidepressants.
Highlights
The most commonly used antidepressant drugs, the selective serotonin reuptake inhibitors (SSRIs), have been shown to act in part by promoting a series of synaptic, cellular and network adaptations in the dentate gyrus (DG) [1,2,3,4]
To investigate the presence of 5-HT receptors on hippocampal PV neurons, we used a translating ribosome affinity purification (TRAP) approach and generated PV-TRAP conditional knock-in mice. 5-HT5A receptors are enriched in hippocampal PV neurons (Fig. 1a), but not in CCK- or in other GAD65-expressing cells (Fig. 1b)
After 3 weeks of chronic treatment with the SSRI fluoxetine (Flx; 0.167 mg/ml in drinking water), application of 5-HT led to a hyperpolarizing response of the membrane potential of PV neurons (Fig. 1c, d). This response to 5-HT was blocked by the 5-HT5A receptor antagonist SB 699,551 and was abolished in mice in which the 5-HT5A receptor was conditionally deleted from PV neurons both before and after the antidepressant treatment (Fig. 1c, d)
Summary
The most commonly used antidepressant drugs, the selective serotonin reuptake inhibitors (SSRIs), have been shown to act in part by promoting a series of synaptic, cellular and network adaptations in the dentate gyrus (DG) [1,2,3,4]. Two different classes of serotonin receptors, 5-HT1B and 5-HT2A, located on cholecystokinin (CCK)-expressing inhibitory interneurons, are critical for both the acute and chronic responses to SSRIs [5]. The activation of PV interneurons promotes the survival and development of newborn granule cells [6], and this process is associated with chronic SSRI treatment [3], but whether PV neurons are directly regulated by 5-HT has not been determined
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