Abstract
Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.
Highlights
The brain serotonin (5-HT) system has been implicated in emotion regulation and related psychopathological states, including anxiety, depression, impulsivity, and aggression
In these conditions of pharmacological isolation, the basal firing activity of 5-HT neurons reflects their intrinsic pacemaker activity, a characteristic that is difficult to study in vivo, where the firing activity is under control of both autoinhibition and synaptic input
COMPARISON OF 5-HT1A RECEPTOR SENSITIVITY ACROSS GENOTYPES Since 5-HT neuron autoinhibition is mediated by 5-HT1A receptors, we investigated the functional response of 5-HT neurons to the 5-HT1A receptor agonist R(+)-8-OH-DPAT in different genotypes
Summary
The brain serotonin (5-HT) system has been implicated in emotion regulation and related psychopathological states, including anxiety, depression, impulsivity, and aggression (reviewed in Lesch et al, 2012). 5-HT neurons in the DRN are known to exhibit spontaneous regular firing activities (Trulson and Jacobs, 1979; Vandermaelen and Aghajanian, 1983). In waking states, firing of 5-HT neurons is facilitated by noradrenergic input (Levine and Jacobs, 1992). The role of 5-HT1A receptors in suppression/regulation of 5-HT neuron firing activity is considered to be relevant to the pathophysiology of disorders of emotion regulation (Pineyro and Blier, 1999; Sharp et al, 2007). The importance of 5-HT1A receptor function is further supported by the presumed mechanism of selective 5-HT reuptake inhibitor (SSRI) antidepressant action (Artigas et al, 1996; Pineyro and Blier, 1999). After acute administration of SSRI, extracellular 5-HT concentrations transiently increase and activate 5-HT1A autoreceptors, inhibiting firing of 5-HT neurons.
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