Mechanisms of 5‐HT_1A receptor‐mediated transmission in dorsal raphe serotonin neurons

Abstract

Key pointsr In the dorsal raphe nucleus, it is known that serotonin release activates metabotropic 5-HT 1A autoreceptors located on serotonin neurons that leads to an inhibition of firing through the activation of G-protein-coupled inwardly rectifying potassium channels.r We found that in mouse brain slices evoked serotonin release produced a 5-HT 1A receptor-mediated inhibitory postsynaptic current (IPSC) that resulted in only a transient pause in firing.r While spillover activation of receptors contributed to evoked IPSCs, serotonin reuptake transporters prevented pooling of serotonin in the extrasynaptic space from activating 5-HT 1A -IPSCs.r As a result, the decay of 5-HT 1A -IPSCs was independent of the intensity of stimulation or the probability of transmitter release.r These results indicate that evoked serotonin transmission in the dorsal raphe nucleus mediated by metabotropic 5-HT 1A autoreceptors may occur via point-to-point synapses rather than by paracrine mechanisms. AbstractIn the dorsal raphe nucleus (DRN), feedback activation by Gα i/o -coupled 5-HT 1A autoreceptors reduces the excitability of serotoninergic neurons, which decreases serotonin release both locally within the DRN and in projection regions. Serotonin transmission within the DRN is thought to occur via transmitter spillover and paracrine activation of extrasynaptic receptors. Here, we tested the volume transmission hypothesis in mouse DRN brain slices by recording 5-HT 1A receptor-mediated inhibitory postsynaptic currents (5-HT 1A -IPSCs) generated by the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs). We found that in the DRN of ePET1-EYFP mice, which selectively express enhanced yellow fluorescent protein in serontonergic neurons, the local release of serotonin generated 5-HT 1A -IPSCs in serotonin neurons that rose and fell within a second. The transient activation of 5-HT 1A autoreceptors resulted in brief pauses in neuron firing that did not alter the overall firing rate. The duration of 5-HT 1A -IPSCs was primarily shaped by receptor deactivation due to clearance via serotonin reuptake transporters. Slowing diffusion with dextran prolonged the rise and reduced the amplitude the IPSCs and the effects were potentiated when uptake was inhibited. By examining the decay kinetics of IPSCs, we found that while spillover may allow for the activation of extrasynaptic receptors, efficient uptake by serotonin reuptake transporters (SERTs) prevented the pooling of serotonin from prolonging the duration of transmission when multiple inputs were active. Together the results suggest that the activation of 5-HT 1A receptors in the DRN results from the local release of serotonin rather than the extended diffusion throughout the extracellular space. Abbreviations 5-HT, serotonin; DRN, dorsal raphe nucleus; GIRK, G-protein coupled, inwardly rectifying potassium channel; IPSC, inhibitory postsynaptic current; SERT, serotonin reuptake transporter; sIPSC, spontaneous inhibitory postsynaptic current.

An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells

“…Indeed, 5-HT receptors inhibit I Ca in neurons (Bayliss et al, 1997b; Foehring, 1996; Penington and Kelly, 1990) and several GPCRs use this mechanism in adrenal chromaffin cells, including P2Y purinergic, μ-opioid, prostaglandin EP3, and alpha adrenergic receptors (Albillos et al, 1996; Brede et al, 2003; Carabelli et al, 1998; Currie and Fox, 1996; Jewell et al, 2011). However, we found the 5-HT 1A receptor had no effect on I Ca in chromaffin cells (figure 6), and also had no effect on GIRK channels (figure 6) which help control membrane excitability in the CNS (Courtney and Ford, 2016; Luscher et al, 1997; Penington et al, 1993). Using fluorescent Ca 2+ imaging we confirmed that Ca 2+ entry was unaltered and intracellular Ca 2+ handling (clearance, release from intracellular stores, etc.)…”

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

“…Additional future studies could include pharmacological investigation of potential receptors (GR, glutamate, GABA) responsible for the effect of chronic CORT on intrinsic excitability and also how the DR neurons respond to bath application of 5‐HT or a 5‐HT 1A agonist following chronic CORT administration. The latter experiment would provide insight into the effect of glucocorticoid excess on the autoregulation of these target‐specific populations and represents an area of particular interest because most antidepressant medications are thought to achieve therapeutic efficacy through accumulation of 5‐HT within the DR and desensitization of somatodendritic 5‐HT 1A inhibitory autoreceptors on serotonergic projection neurons (Artigas, ; Courtney & Ford, ).…”

Positive regulation of raphe serotonin neurons by serotonin 2B receptors

“…SSRI antidepressants, which have a more limited effect on 5-HT release from dendrites than from the soma and terminals, markedly increase extracellular 5-HT in DRN that involves both somatic and dendritic release [45]. The 5-HT released within DRN induces feedback inhibition of 5-HT neuron firing activity by stimulation of somatodendritic 5-HT 1A -negative autoreceptors, which results from local release rather than extended diffusion of 5-HT throughout the extracellular space [46]. We found that the hypothermic response to 8-OHDPAT, known to be mediated by 5-HT 1A autoreceptors but not heteroreceptors in mice [35], is attenuated by pretreatment with the 5-HT 2B receptor agonist BW723C86.…”