Modulation of Firing and Synaptic Transmission of Serotonergic

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REVIEW ARTICLE published: 23 May 2013 doi: 10.3389/fnint.2013.00040 Modulation of ﬁring and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels

Takashi Maejima, Olivia A. Masseck, Melanie D. Mark and Stefan Herlitze* Department of Zoology and Neurobiology, Ruhr-University Bochum, Bochum, Germany

Edited by: Serotonergic neurons project to virtually all regions of the central nervous system and Kae Nakamura, Kansai Medical are consequently involved in many critical physiological functions such as mood, sexual University, Japan behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, Reviewed by: breathing, and reproductive success. Therefore, serotonin release and serotonergic David M. Lovinger, National Institutes of Health, USA neuronal activity have to be precisely controlled and modulated by interacting brain circuits Evan Deneris, Case Western Reserve to adapt to speciﬁc emotional and environmental states. We will review the current University, USA knowledge about G protein-coupled receptors and ion channels involved in the regulation of *Correspondence: serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic Stefan Herlitze, Department of neurons and its transmitter release and will discuss the latest methods for controlling the Zoology and Neurobiology, Ruhr-University Bochum, modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro Universitätsstr. 150, ND 7/31, and in vivo. D-44780 Bochum, Germany. e-mail: [email protected] Keywords: 5-HT system, GPCRs, auto-regulation, hetero-regulation, optogenetics

INTRODUCTION densely packed in the midline and some 5-HT neurons are scat- The serotonergic system consists of a small number of neurons tered in the periphery. Within the DRN and MRN 5-HT neurons that are born in the ventral regions of the hindbrain (Deneris and project to deﬁned target area in brain (Adell et al., 2002; Lechin View metadata, citation and similar papers at core.ac.uk brought to you by CORE Wyler, 2012). In the adult nervous system, serotonergic neurons et al., 2006). For example, DRN 5-HT neurons innervate the pre- [5-HT (5-hydroxytryptamine) neurons] are located in the nine frontal cortex, lateral septum, and ventral hippocampus, while provided by Frontiers - Publisher Connector raphe nuclei that are restricted to the basal plate of the mid- MRN 5-HT neurons innervate the temporal cortex, medial sep- brain, pons, and medulla (Dahlstrom and Fuxe, 1964). 5-HT tum, and dorsal hippocampus. Afferent projections to the raphe neurons located in the rostral raphe nuclei, such as the dorsal nuclei are diverse and include acetylcholine (ACh) from the lat- raphe nucleus (DRN) and the median raphe nucleus (MRN), give erodorsal tegmental nucleus, dopamine from the substantia nigra rise to the majority of the serotonergic ascending ﬁbers into the and ventral tegmentum area, histamine from tuberomammil- forebrain including cerebral cortex, limbic system, and basal gan- lary hypothalamic nucleus, noradrenaline (NA) from the locus glia (Jacobs and Azmitia, 1992). The activity of the serotonergic coeruleus, serotonin itself from the raphe nuclei and several system is regulated via transmitter release from local interneurons neuropeptides as well as excitatory glutamatergic and inhibitory and/or afferents to the raphe nuclei (hetero-regulation), via mech- GABAergic inputs. Glutamatergic inputs come from several nuclei anisms arising from 5-HT neurons themselves (auto-regulation), including medial prefrontal cortex and lateral habenula nucleus and potentially via alterations in the extracellular milieu (e.g., (Aghajanian and Wang, 1977; Celada et al., 2001; Adell et al., increase in CO2; Pineyro and Blier, 1999; Richerson, 2004). In this 2002; Bernard and Veh, 2012). Some inputs make direct contacts review, we will discuss G protein-coupled receptors (GPCRs) and with 5-HT neurons, while others project onto local GABAergic ion channels located at somatodendritic and presynaptic regions interneurons that provide feedforward inhibitory input to 5-HT of 5-HT neurons in the DRN and MRN that contribute to the mod- neurons (Sharp et al., 2007). In addition to the local GABAergic ulation of 5-HT neuronal activity and 5-HT release (Figure 1). interneurons located in the raphe nuclei and in the neighboring The DRN and MRN are the primary nuclei of 5-HT projections periaqueductal gray area, extrinsic GABAergic projections have to forebrain and provide the neural substrate to communicate been suggested (Gervasoni et al., 2000). The responsiveness of 5- between global forebrain and other neuromodulatory systems by HT neurons to each of the inputs differs between DRN and MRN, sending a wide range of 5-HT projections and receiving a wide and also within the subnuclei of the DRN (Adell et al.,2002; Lechin variety of afferents (Jacobs and Azmitia, 1992). The DRN is located et al., 2006). The differences in responsiveness most likely depend right beneath the posterior part of cerebella aqueduct and con- on differences in the strength of the afferent inputs for each of tains about half of all 5-HT neurons in the central nervous system the nuclei and subnuclei and also on the expression and types of (CNS), which can be further divided into six regions: rostral, cau- the ionotropic and metabotropic receptors in 5-HT neurons. Fur- dal, dorsomedial, ventromedial, interfascicular, and lateral parts. thermore, the intrinsic membrane excitability of 5-HT neurons The MRN is located at the ventral expansion of the DRN or the has been reported to differ in the distinct raphe nuclei (Beck et al., midline of the pontine tegmentum where many 5-HT neurons are 2004; Crawford et al., 2010). Importantly, beyond the anatomical

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and physiological differences, it has been reported that subpop- The predominant 5-HT receptors at the presynaptic termi- ulation of 5-HT neurons have distinct implications in specific nal are the 5-HT1B/1D receptors. 5-HT1B/1D receptorshavebeen physiological function and behavior (Abrams et al., 2004; Lechin shown to inhibit 5-HT release from the axonal varicosities as et al., 2006; Hale and Lowry, 2010). demonstrated with electrophysiological experiments (Sprouse and Aghajanian, 1987; Boeijinga and Boddeke, 1993; Morikawa et al., AUTO-REGULATION 2000), probably due to inhibition of Ca2+ influx through voltage- The midbrain 5-HT neurons elicit spontaneous action potentials gated Ca2+ channels such as P/Q-type and N-type Ca2+ channel (APs), with a regular, slow firing pattern (1–5 APs/s; Aghajanian (Kimura et al., 1995; Harvey et al., 1996). The 5-HT1B receptors and Vandermaelen, 1982; Vandermaelen and Aghajanian, 1983). have been shown to underlie presynaptic autoinhibition of 5- 5-HT released from 5-HT neurons act either on the 5-HT neu- HT release in which 5-HT1A-mediated slow IPSPs are reduced by ron itself or on the target circuits. There are several ways how previous released 5-HT activating presynaptic 5-HT1B receptors 5-HT neurons may receive 5-HT. First, dendrodendritic synapses (Morikawa et al., 2000). In addition, 5-HT1B receptorshavebeen releasing 5-HT have been described in raphe nuclei between 5-HT suggested to up-regulate 5-HT reuptake by serotonin transporters neurons. Second, recurrent axonal collaterals have been suggested (Xie et al., 2008; Hagan et al., 2012) and 5-HT synthesis by itself to back-propagate to the raphe nucleus itself to release 5-HT. might be under the control of 5-HT1B (Hjorth et al., 1995). Thus, Finally, 5-HT neurons between different raphe nuclei such as 5-HT1B autoreceptors may have the ability to control 5-HT release DRN and MRN communicate with each other via 5-HT (for independently from the actual firing rate. review, see Adell et al., 2002; Harsing, 2006; Lechin et al., 2006). 5-HT1F receptor mRNA has also been detected in the raphe Indeed electrical stimulation in DRN slice preparations induces nuclei (Bruinvels et al., 1994). Since 5-HT1F receptorshavea 5-HT1A receptor-mediated slow inhibitory postsynaptic poten- high affinity for sumatriptan, a 5-HT1B/1D agonist, and the tials (IPSPs) in 5-HT neurons (Pan et al., 1989; Morikawa et al., sumatriptan-induced reduction in 5-HT release (monitored by 2000), demonstrating 5-HT release in the proximity of 5-HT voltammetry in brain slices) could not be blocked by 5-HT1A/1B/1D neurons. receptor antagonists, 5-HT1F had been suggested as a possible can- Once 5-HT is released, 5-HT receptors will be activated. Seven didate of a serotonergic autoreceptor in the MRN (Hopwood and subgroups of 5-HT receptors encoding ionotropic as well as Stamford, 2001). metabotropic receptors have been described (5-HT1–5-HT7), with While the expression and function of 5-HT1 receptors has been 15 total variants identified to date (Barnes and Sharp, 1999; Hoyer directly demonstrated in 5-HT neurons, involvement of other 5- et al., 2002; Kroeze et al., 2002). The 5-HT GPCRs can be divided HT receptors such as 5-HT2, 5-HT3, and 5-HT4−7 is less clear and into three major subgroups depending on which G protein sig- may differ among species, the developmental stage of the animal naling pathway they activate. 5-HT1 receptors couple mainly to and 5-HT neuron subtypes. the Gi/o pathway; 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors 5-HT2 receptors are functionally expressed in particular on couple to the Gs pathway; and 5-HT2 receptors activate the Gq/11 GABAergic interneurons in the DRN, since activation of 5- pathway. The 5-HT3 receptors are ligand-gated ion channels. HT2A/2C receptors increase fast inhibitory postsynaptic current 5-HT1A, 5-HT1B, and 5-HT1D receptors are found on soma- (IPSC) frequency in 5-HT neurons and reduce 5-HT neuronal fir- todendritic and axonal region of 5-HT neurons (McDevitt and ing as electrophysiologically measured in brain slices (Liu et al., Neumaier, 2011). All three receptors act as negative feedback effec- 2000; Leysen, 2004). 5-HT2 receptor mRNA and proteins have tors for 5-HT neuronal firing and 5-HT release (Andrade, 1998). been identified in the DRN and embryonic 5-HT neurons (Wright Somatodendritically located 5-HT1A receptors down-regulate the et al., 1995; Clemett et al., 2000; Wylie et al., 2010). Additionally, 5- firing rate of 5-HT neurons via activation of G protein-coupled HT2 receptors have been postulated to increase 5-HT1A-mediated inwardly rectifying potassium channels (GIRK) leading to mem- responses in 5-HT neurons (Kidd et al., 1991). However, a direct brane hyperpolarization, and reduction or complete block of modulatory effect of 5-HT2 in 5-HT neurons has not been AP firing (Colino and Halliwell, 1987; Sprouse and Aghajanian, demonstrated. 1987; Blier et al., 1989; Hjorth and Sharp, 1991; Penington et al., The 5-HT3 receptors have also been suggested to act as presy- 1993; Stamford et al., 2000). In addition, 5-HT1A receptors inhibit naptic autoreceptors in serotonergic nerve terminals. Although 2+ voltage-gated Ca channels of the N- and P/Q-type in 5-HT 5-HT3 receptors have been shown to enhance 5-HT release in neurons, as application of a selective 5-HT1A agonist dimin- various brain areas including the raphe nuclei as monitored ishes somatic Ca2+ channel currents (Penington and Kelly, 1990; by [3H]5-HT assays (Bagdy et al., 1998), there is no direct Penington et al., 1992; Bayliss et al., 1997b). The functional conse- immunohistochemical and electrophysiological evidence of the 2+ quence of Ca channel inhibition is an increase in the firing rate presence of 5-HT3 receptors in 5-HT neurons (van Hooft and due to reduction in the afterhyperpolarization, which may involve Vijverberg, 2000). 2+ + Ca activated-K channel (Bayliss et al., 1997b). The physio- For the Gs protein-coupled 5-HT4−7 receptors, mainly indirect logical role of the differential effects of 5-HT1A receptorsonthe evidence exists for an autoregulatory role of these GPCRs in 5-HT AP firing has not been addressed so far, but may involve input neurons. 2+ specificity due to 5-HT1A/GIRK and 5-HT1A/Ca channel colo- 5-HT4 receptors seem to be located somatodendritically and calization in specific subcellular domains and/or differences in the presynaptically. A presynaptic potentiating effect of 5-HT4 recep- regulatory properties of heterogeneous 5-HT neurons within and tor on glutamate release, which can be counteracted by 5- among different raphe nuclei (Calizo et al., 2011). HT1A receptor-mediated inhibitory action, has been described in

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FIGURE 1 | Intrinsic somatodendritic and presynaptic modulation of ion channels. Gq/11 pathway activation can lead to the activation of action potential (AP) firing and transmitter release in 5-HT neurons. (A) non-selective cation channels or inhibition of K+ conductance. In addition, the AP firing of 5-HT neurons is modulated by GPCRs and ion channels. AP firing activation of L-type Ca2+ channels via protein kinase C (PKC) can most likely is reduced (red arrows) via activation of GPCRs coupling to the Gi/o pathway increase membrane depolarization and transcription. (B) 5-HT release of 5-HT or activation of inhibitory ligand-gated ion channels. Gi/o pathway activation neurons is also modulated by GPCRs and ion channels. 5-HT release is 2+ can lead to the activation of GIRK channels, inhibition of voltage-gated Ca reduced (red arrow) via activation of GPCRs coupling to the Gi/o pathway. Gi/o 2+ channels or increase in GABAA receptor currents. In addition, Gq/11 activation pathway activation leads to the inhibition of presynaptic Ca channels, can lead to synthesis of endocannabinoids, which inhibit transmitter release reduction in Ca2+ influx and therefore reduction in transmitter release. 5-HT onto 5-HT neurons. AP firing is increased (blue arrows) via activation of release is increased (blue arrows) via activation of GPCRs coupling to the Gs GPCRs coupling to the Gq/11 pathway or activation of excitatory ligand-gated pathway and via opening of excitatory, ligand-gated ion channels.

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hippocampal neurons (Kobayashi et al., 2008). Since neurotrans- needs to be defined and investigated (for a complete list, see Wylie mitter release of various transmitters including 5-HT is modulated et al., 2010). We will summarize recent findings on the intrinsic by 5-HT4 agonists, a presynaptic localization of 5-HT4 receptors hetero-regulation of the serotonergic transmitter system. on 5-HT neurons seems possible (Mengod et al., 2010). While the function of 5-HT5 receptors in the CNS has not been GABA, GLYCINE, AND GLUTAMATE thoroughly studied, two studies suggest a role of 5-HT5 receptors 5-HT neurons within the raphe nuclei receive in particular for modulating 5-HT neurons. First, 5-HT5B receptor mRNA, a GABAergic but also glutamatergic input. As expected, the receptor which is expressed in rodents but not in humans, is colo- GABAergic input onto 5-HT neurons reduces the neuronal firing, calized with the mRNA of 5-HT transporter in the DRN (Serrats while glutamatergic input increases the firing activity (Pan and et al., 2004). Second, block of 5-HT5A receptors in the DRN atten- Williams, 1989; Levine and Jacobs, 1992; Becquet et al., 1993a,b; uates the 5-carboxamidotryptamine (5-CT; non-selective agonist for review, see Adell et al., 2002; Harsing, 2006). These effects have in particular for 5-HT1A/1B/1D receptors) induced reduction of 5- been mainly attributed to the expression of ionotropic GABA and HT neuronal firing but fail to affect 5-HT release measured using glutamate receptors (GluRs) in 5-HT neurons (Tao and Auerbach, fast cyclic voltammetry in vitro (Thomas et al., 2006). The data 2000; Gartside et al., 2007), which is in agreement with the expres- suggest an autoreceptor modulation of 5-HT neurons via 5-HT5A sion of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic receptors. acid (AMPA), N-methyl-D-aspartate (NMDA), kainate receptors 5-HT6 and 5-HT7 receptor protein and mRNA have been [GluR 1,2; NMDA-R-2B, kainate receptor 5 (Grik5)] as well as detected in cells in the raphe nuclei including the DRN (Ruat GABAA receptor subunits (GABAA β1–3 and γ2) in embryonic et al., 1993; To et al., 1995; Gustafson et al., 1996; Woolley et al., 5-HT neurons (Wylie et al., 2010). Interestingly, the glycine recep- 2004; see also Gerard et al., 1997; Hamon et al., 1999), but a func- tor α1 and β subunits have also been identified in human brain tional role as autoreceptors for modulating 5-HT neurons could and mice embryonic 5-HT neurons (Baer et al., 2003; Wylie et al., not be demonstrated so far (Bourson et al., 1998; Roberts et al., 2010). Indeed the DRN receives input from glycinergic fibers 2001). (Rampon et al., 1996, 1999) to inhibit 5-HT neuronal firing and 5- Thus, the auto-regulation of 5-HT neuronal firing is in par- HT release (Gallager and Aghajanian, 1976; Wang and Aghajanian, ticular regulated by 5-HT1A receptors via activation of the Gi/o 1977; Becquet et al., 1993a). + 2+ pathway and opening K and closing Ca conductance. At the The modulation of 5-HT neurons by GABAB receptors has presynaptic terminal, 5-HT1B/1D receptor activation reduces 5-HT been addressed in various studies. In general, activation of GABAB release most likely via Gi/o protein-mediated inhibition of presy- receptor by selective agonists decreases 5-HT release (Becquet 2+ naptic Ca channels. In addition, potentiation of 5-HT release et al., 1993b). The decrease of 5-HT release by GABAB receptors by activating 5-HT4 receptors via the Gs pathway seems possible. located within 5-HT neurons is most likely mediated via activa- Since other 5-HT receptor mRNAs have been detected in 5-HT tion of GIRK channels leading to a reduction in AP firing (Innis neurons, other autoregulatory mechanisms may exist in subgroups and Aghajanian, 1987; Williams et al., 1988; Bayliss et al., 1997a; of 5-HT neurons or during different developmental stages of the Cornelisse et al., 2007). Within 5-HT neurons, GABAB receptors serotonergic transmitter system. In particular, animal models for are located extrasynaptically, suggesting that spillover of GABA the selective activation of these GPCRs during development will during high activity of GABAergic neurons would modulate 5- further elucidate the modulatory role of other 5-HT receptors in HT neuronal activity within raphe nuclei (Varga et al., 2002). the auto-regulation of 5-HT neuronal firing and 5-HT release. On the other hand, there is little information about modulatory effects of metabotropic GluRs (mGluRs) in 5-HT neurons HETERO-REGULATION so far. Although administration of group II mGluR (mGluR2/3) 5-HT modulates various complex behaviors and therefore the antagonist has been reported to increase 5-HT neuronal activity, serotonergic transmitter system receives feedback and feedforward an indirect effect on presynaptic excitatory neurons seems to be information from other brain areas and networks involved in reg- involved (Kawashima et al., 2005). ulating the different behaviors (Adell et al., 2002; Lechin et al., 2006; Sharp et al., 2007). Thus, the hetero-regulation of the 5-HT CORELEASE OF GLUTAMATE OR GABA FROM 5-HT NEURONS neurons involves various transmitter systems. Previous reports have suggested the possibility of glutamate release Forty-nine different GPCRs belonging to all four GPCR sub- from 5-HT neurons based on the presence of vesicular glutamate families were identified in postmitotic embryonic 5-HT neurons transporter type 3 in a subset of 5-HT neurons (Gras et al., 2002; using microarray expression profiling (Wylie et al., 2010). These Amilhon et al., 2010). Using optogenetic techniques, the core- GPCRs include adrenergic, calcitonin, cannabinoid, GABA, his- lease of glutamate and 5-HT from serotonergic terminals could tamine, opioid, and serotonin receptors. For these transmitter be demonstrated in a serotonergic projection from the MRN to systems, a postnatal modulatory role for 5-HT neurons has been hippocampal GABAergic interneurons (Varga et al., 2009). The described (see below). In addition, other GPCRs such as thrombin, serotonergic fibers make direct synaptic contacts to the GABAer- chemokine, prostaglandin E, melanin-concentrating hormone, gic neurons and exert fast synaptic transmission mediated by cadherin, and parathyroid hormone receptors as well as frizzled ionotropic GluRs and 5-HT3 receptors. In addition to the glu- (FZD) and smoothened (SMO) homolog and the orphan recep- tamate transporters, GABA and its synthesizing enzyme, glutamic tors (GPR 19, 56, 85, 98, 125 135, 162, and 173) were also identified acid decarboxylase (GAD) have also been reported in subsets but a physiological role for their modulation of 5-HT neurons still of 5-HT neurons, suggesting the corelease of GABA and 5-HT

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(Nanopoulos et al., 1982; Belin et al., 1983; Fu et al., 2010; Hioki coupling might be explained by the heterodimerization between et al., 2010; Shikanai et al., 2012). However, vesicular inhibitory D1- and D2-like receptors (Rashid et al., 2007; Hasbi et al., 2010). amino acid transporter which is necessary for filling synaptic vesi- It has to be noted that the experiments suggesting the modula- cles with GABA was absent in 5-HT/GAD67 positive neurons and tion of 5-HT neurons by intrinsic D2-like receptors have been their projections, suggesting that GABA may be released by non- performed with relatively high concentrations of quinpirole and vesicular mechanisms such as a reverse transport through GABA sulpiride in in vitro preparations. Therefore, the experiments have transporters (Shikanai et al., 2012). Thus, 5-HT axonal projections to be interpreted carefully. have a potential to modulate the neuronal activity in target areas using at least three different transmitters, i.e., 5-HT, glutamate, NORADRENALINE and GABA. It is intriguing to speculate that the auto-regulation of 5-HT neurons in the raphe nuclei receive noradrenergic input 5-HT neurons itself might be modulated by corelease of glutamate in particular from the locus coeruleus (Adell et al., 2002; Lechin and GABA. et al., 2006). α1 and α2 adrenergic receptor mRNA and protein have been detected in the DRN and MRN (Unnerstall et al., 1985; ACETYLCHOLINE Rosin et al., 1993; Scheinin et al., 1994; Talley et al., 1996; Day et al., The DRN also receives cholinergic input from the laterodorsal 1997; Strazielle et al., 1999). α1 and α2 adrenergic receptors couple tegmental nucleus (Wang et al., 2000). Modulation of 5-HT neu- to the Gq/11 and Gi/o pathway, respectively. Therefore depending rons by ACh mainly involves nicotinic ACh receptors (nAChRs) on pathway activation, an increase or decrease in 5-HT neuronal and can increase 5-HT neuronal firing (Mihailescu et al., 2002) activity and 5-HT release can be postulated if adrenergic recep- for example, via presynaptic modulation of glutamate release tors are expressed in 5-HT neurons. Early studies revealed that NA (Garduno et al., 2012) or via opening of nAChR expressed in causes an increase in 5-HT neuronal firing in DRN. This effect 5-HT neurons (Galindo-Charles et al., 2008; Chang et al., 2011). has been suggested to be mediated via activation of α1 adreno- Very limited information is available for the expression and func- ceptors (presumably α1B adrenoceptor subtype) located on 5-HT tion of muscarinic ACh receptors (mAChRs) in 5-HT neurons. neurons (Vandermaelen and Aghajanian, 1983; Day et al., 1997) mAChR-M1 receptors (Gq/11) might be expressed on serotoner- and may involve the suppression of a 4-aminopyridine sensitive + gic projections into the hippocampus (Rouse and Levey, 1996) K conductance (IA; Aghajanian, 1985). In vivo experiments sug- and application of mAChR antagonist, atropine into the DRN gest that α1 adrenoceptors are tonically activated by endogenous enhances antidepressant-like 5-HT1A agonist effects (Haddjeri NA (Adell and Artigas, 1999; Pudovkina et al., 2003). In con- 3 et al., 2004), which may involve M2 (Gi/o) but not M1 (Gq/11) trast, 5-HT release detected by voltammetry or [ H]5-HT assay receptors (Haddjeri et al., 2000). Nevertheless a detailed and direct in the DRN slice preparation is inhibited by NA, an effect which demonstration of the involvement of mAChRs in 5-HT neurons has been attributed to α2 adrenoceptors (involving α2A adreno- is essential. ceptor subtype) and also perhaps indirectly to α1 adrenoceptors (Frankhuijzen et al., 1988; Hopwood and Stamford, 2001). Since DOPAMINE α2 receptors couple to the Gi/o pathway, 5-HT release and 5-HT The 5-HT neurons of the DRN reciprocally interact with neuronal firing could be reduced via α2 adrenoceptors located at the dopaminergic mesencephalic transmitter system involving the soma or presynaptic terminal of 5-HT neurons itself (Hop- dopamine receptors. D1-like receptors (D1 and D5) couple to wood and Stamford, 2001), or via inhibition of NA release at the Gs pathway, while dopamine D2-like receptors (D2−4)have noradrenergic synaptic terminals lowering the effective NA con- been described to couple to the Gi/o pathway. In the DRN, D2 centration for α1 adrenoceptors/Gq signaling pathway activation. and D3 receptor expression has been detected so far, with very The direct effect of α2 adrenoceptors in 5-HT neurons is sup- little or no expression of D1-like receptors (Bouthenet et al., 1987; ported by the fact that embryonic 5-HT neurons express α2A Dawson et al., 1988; Cortes et al., 1989; Wamsley et al., 1989; adrenoceptors (Wylie et al., 2010). Yokoyama et al., 1994; Suzuki et al., 1998). Dopamine increases 5-HT neuronal firing in DRN in vivo and in slice electrophysio- HISTAMINE logical recording, and also increases 5-HT release detected by in There are four histamine receptors (H1−4), which couple to dif- vivo microdialysis in DRN and other brain areas (Ferre and Arti- ferent G protein pathways, i.e., H1 (Gq/11), H2 (Gs), H3, and H4 gas, 1993; Ferre et al., 1994; Matsumoto et al., 1996; Mendlin et al., (Gi/o). Early studies suggested that histamine reduces the firing 1998; Haj-Dahmane, 2001; Martin-Ruiz et al., 2001). The modu- of 5-HT neurons in the DRN (Lakoski and Aghajanian, 1983) latory effects on 5-HT neurons have been shown to be mediated by via H2 receptors (Lakoski et al., 1984). Since H2 couples to the D1- and D2-like receptors located outside the DRN (Martin-Ruiz Gq/11 pathway, the results suggest that H2 receptors are localized et al., 2001)orbydirectactivationofD2 receptors expressed in on GABAergic terminals. Later findings showed that histamine 5-HT neurons (Haj-Dahmane, 2001). Activation of D2-like recep- increased 5-HT neuronal firing in the DRN via activation of H1 tors in 5-HT neurons leads to membrane depolarization, involving receptors and the opening of a non-selective cation conductance activation of G proteins, phospholipase C, and a non-selective through Gq/11 signaling pathways (Barbara et al., 2002; Brown cation current, most likely mediated by a transient receptor poten- et al., 2002). Expression profiling in mouse embryos suggested tial (TRP) channel (Aman et al.,2007). The D2-like receptor effects the expression of H3 receptors in 5-HT neurons, which is consis- in 5-HT neurons suggest that D2-like receptors may activate the tent with high mRNA levels in the DRN (Lovenberg et al., 1999; Gq/11 rather than the Gi/o signaling pathway. The Gq/11 protein Drutel et al., 2001; Pillot et al., 2002). However, the low binding

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of a H3 receptor selective radioligand in the DRN suggests that and corticotropin-releasing factor (CRF). Among these, various H3 receptors are mainly functional at the presynaptic terminal peptide receptors have been identified and functionally described of 5-HT projections (Pillot et al., 2002). Indeed increasing lev- in 5-HT neurons. els of histamine decrease 5-HT release detected by an in vivo electrochemical technique (Hashemi et al., 2011). BOMBESIN To date three types of bombesin receptors have been described, ENDOCANNABINOIDS i.e., the neuromedin B (NMB) receptor (BB1 receptor), the gastrin- The cannabinoid receptor family consists of two subtypes, CB1 and releasing peptide (GRP) receptor (BB2 receptor) and the bombesin CB2. Modulation of neuronal activity is mainly exerted via CB1, receptor subtype 3 (BRS-3 or BB3 receptor; Jensen et al.,2008). The which couples to the Gi/o protein (Howlett et al., 1986) and proba- NMB receptors are functionally expressed in 5-HT neurons in the bly also to the Gs pathway (Glass and Felder, 1997). CB1 receptors DRN (Pinnock et al., 1994; Woodruff et al., 1996). BB1 receptor are localized in particular at presynaptic terminals, where they activation leads to an increase in 5-HT neuronal firing via sup- inhibit presynaptic Ca2+ influx and reduce transmitter release via pression of K+ current, involving most likely the activation of the endocannabinoid (eCB)-mediated retrograde signaling (Maejima Gq/11 pathway (Benya et al., 1992; Woodruff et al., 1996) and as a et al., 2001). CB1 receptors are expressed in serotonergic fibers consequence, an increase in 5-HT release to projection site such (Haring et al., 2007; Ferreira et al., 2012) and their mRNA is found as the hippocampus, which is monitored by in vivo microdialysis early in development (Wylie et al., 2010). 5-HT release in pro- (Merali et al., 2006). jection areas from the DRN is reduced by activation of CB1 as monitored by microdialysis (Egashira et al., 2002) and [3H]5-HT CALCITONIN assay (Nakazi et al., 2000; Egashira et al., 2002), and increased by Calcitonin receptor (CalcR) mRNA has been localized in 5-HT inhibition of CB1 in vivo and in vitro (Darmani et al.,2003; Tzavara neurons in the DRN (Nakamoto et al.,2000), which is in agreement et al., 2003; Aso et al., 2009). Studies in CB1 knock-out animals with the expression profiling studies of postmitotic embryonic 5- and chronic activation of CB1 receptors in vivo suggest that CB1 HT neurons (Wylie et al., 2010). The CalcR couples to the Gs may regulate the function and expression of 5-HT1A receptors pathway (Hay et al., 2005) and Gq/11 pathway (Offermanns et al., (Aso et al., 2009; Moranta et al., 2009; Zavitsanou et al., 2010). 1996). Since high levels of amylin binding sites are detected in Interestingly, 5-HT neurons itself synthesize eCBs in an activity- the DRN (Sexton et al., 1994) and mRNA for CGRP has been dependent manner (Haj-Dahmane and Shen, 2009, 2011). eCB localized in 5-HT positive axon terminals in monkeys (Arvidsson release from 5-HT neurons can be induced by orexin-B leading et al., 1990), it is most likely that CalcR assemble with receptor to the activation of orexin (OX) receptors via the Gq/11 pathway activity-modifying proteins (RAMPs) in 5-HT neurons to respond (Liu et al., 2002b; Haj-Dahmane and Shen, 2005). It has been to the various peptide transmitters (i.e., CGRP, adrenomedullin, therefore speculated that the activity-dependent activation of the and amylin; Tilakaratne et al., 2000). A direct function of CalcR in Gq/11 pathway in general may lead to the production of eCBs in 5-HT neurons has not yet been demonstrated. However, injection 5-HT neurons (Haj-Dahmane and Shen, 2011). Within the DRN of CGRP into rats induces anxiety-like behaviors and increases eCBs mainly act on glutamatergic terminals and probably also on c-Fos expression in the DRN (Sink et al., 2011). GABAergic terminals (Liu et al., 2002b; Haj-Dahmane and Shen, 2009; Mendiguren and Pineda, 2009; Tao and Ma, 2012), lead- CHEMOKINE RECEPTORS ing to a reduction in glutamate and GABA release onto 5-HT Two subtypes of the 18 identified chemokine receptors have been neurons and therefore changes the activity of the 5-HT neurons detected in microarray analyses from embryonic 5-HT neurons, itself. i.e., Duffy antigen/chemokine (C-X-C motif) receptor 4 (CXCR4; Wylie et al., 2010). CXCR4 is expressed in the majority of 5- FRIZZLED RECEPTORS HT neuron outer membranes in the DRN (Heinisch and Kirby, Four frizzled receptors (FZD1–3 and SMO) have been detected in 2010). So far only an indirect action of CXCR4 for modula- postmitotic embryonic 5-HT neurons (Wylie et al., 2010). These tion of 5-HT neuron has been demonstrated, since application receptors mainly couple to the Wnt signaling cascade and are of the CXCR4 ligands and antagonists modulate GABA and glu- most likely involved in the development and maturation of 5- tamate release onto 5-HT neurons (Heinisch and Kirby, 2010), HT neurons (Simon et al., 2005; Song et al., 2012). However, which is in agreement with the described Gi/o protein-mediated the role of frizzled receptors in 5-HT neurons remains to be inhibition of Ca2+ channels via CXCR4 (Oh et al., 2002). In addi- determined. tion, CX3CR1 is also expressed in 5-HT neurons in the DRN and MRN (Heinisch and Kirby, 2009). Here the CX3CR1 spe- NEUROPEPTIDES cific ligand, fractalkine/CX3CL1 increased evoked IPSC amplitude Dr. Hökfelt’s laboratory demonstrated that various peptide trans- on 5-HT neurons (Heinisch and Kirby, 2009), an effect which mitters are expressed in the DRN with species-specific differences is most likely mediated postsynaptically and not presynaptically. between mice and rats (Fu et al., 2010). The identified neu- The effect is surprising, since CX3CR1 has been described to cou- ropeptides are cholecystokinin (CCK), calcitonin gene-related ple to the Gi/o pathway (Oh et al., 2002), which would inhibit peptide (CGRP), vasoactive intestinal peptide (VIP), somato- synaptic transmitter release and induce paired-pulse facilitation statin, substance P,dynorphin, neurotensin, thyrotropin-releasing (PPF) if activated on GABAergic terminals. Therefore, the CX3CL1 hormone (TRH), enkephalin, galanin, neuropeptide Y (NPY), could increase/modulate GABAA receptor trafficking and GABAA

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receptor currents in 5-HT neurons via activation of CX3CR1. A (Mazarati et al., 2005). Therefore GalR2 receptors may activate 5- signaling function for Duffy antigen remains to be determined. HT neurons via reduction in GABAergic input onto 5-HT neurons and/or via Gq/11-mediated increase in 5-HT neuronal firing. CHOLECYSTOKININ Galanin also modulates 5-HT1A autoreceptor responses in vivo.A The expression of CCK receptors in 5-HT neurons in the DRN has possible mechanism of this modulation could be the heterodimer- also been suggested. Application of CCK increases 5-HT neuronal ization of GalR with 5-HT1A which has been observed in heterologous expression systems (for review, see Kuteeva et al., 2008; firing, which is blocked by the CCK1 antagonist L-364,718 (Boden et al., 1991). In addition, 5-HT release measured as outflow of Borroto-Escuela et al., 2010). [3H]5-HT in cortical slices is increased by CCK-4, which involves HYPOCRETIN–OREXIN CCK2 receptors (Siniscalchi et al., 2001). Both CCK1 and CCK2 The two hypocretin/orexin (OX1 and OX2) receptors are expressed receptors mainly couple to the Gq/11 and Gs pathway (de Weerth et al., 1993; Lee et al., 1993; Ulrich et al., 1993). in tryptophan hydroxylase-positive neurons in the DRN (Brown et al., 2002). Their intracellular signaling targets are rather complex involving activation of Gi/o,Gq/11,Gs, and other G proteins CORTICOTROPIN-RELEASING FACTOR (Scammell and Winrow, 2010). Orexin positive fibers project onto Two CRF (CRF1 and CRF2) receptor subtypes have been described GABAergic as well as 5-HT neurons in the DRN (Peyron et al., in brain and both seem to be localized in GABAergic neurons in 1998). Application of the neuropeptides orexin-A and orexin-B the DRN as well as in 5-HT and non-5-HT neurons with differen- causes a Na+/K+ non-selective cation current in 5-HT neurons tial subcellular localizations (for review, see Valentino et al., 2010). (Brown et al., 2002; Liu et al., 2002b; Kohlmeier et al., 2008), sug- CRF1 and CRF2 couple to the Gs pathway (Chang et al., 1993; Per- gesting that activation of OX1 and OX2 leads to the increase rin et al., 1993; Vita et al., 1993; Lovenberg et al., 1995; Liaw et al., of 5-HT neuronal firing. The neuropeptides also induce GABA 1996) and also the Gq/11 pathway in heterologous expression sys- release onto 5-HT neurons at higher peptide concentrations (Liu tems (Dautzenberg et al., 2004), leading to the assumption that et al., 2002b). In addition, orexin increases the somatic L-type stimulation of CRF1 or CRF2 will increase neuronal firing. Indeed, Ca2+ current in 5-HT neurons in a protein kinase C-dependent activation of CRF1 on GABAergic neurons increases GABA release manner (Kohlmeier et al., 2008). It has therefore been suggested onto 5-HT neurons, while activation of CRF2 elicits an inward cur- that modulation of Ca2+ transients by orexin may be involved in rent in 5-HT neurons (Kirby et al., 2008). Based on the differential the transcriptional regulation of long-term processes (Kohlmeier localization of the CRF receptors within the DRN and its receptor et al., 2008). type-specific action on 5-HT neurons, it has been suggested that at low concentrations of CRF,5-HT neuronal activity is decreased, OPIOIDS while at high concentrations, 5-HT neuronal activity is increased Raphe nuclei receive dynorphinergic, enkephalinergic, and β- (Kirby et al., 2008; Valentino et al., 2010). endophinergic innervation (Adell et al., 2002). These transmitters activate μ, κ and δ opioid receptors, which primarily couple to GALANIN the Gi/o pathway. Injection of morphine into the DRN causes The neuropeptide galanin activates three types of galanin recep- an increase in 5-HT release detected in forebrain microdialysis tors (GalR1−3). GalR1 and GalR2 are highly expressed in the DRN (Tao and Auerbach, 1994). The increase in 5-HT release is most (Melander et al., 1988; Larm et al., 2003; Lu et al., 2005; Sharkey likely mediated via Gi/o protein-mediated inhibition of GABAer- et al., 2008). Moreover, GalR1 expression has also been described gic interneurons in the DRN, involving μ opioid receptors located in 5-HT neurons from rats but not in mice (Xu et al., 1998; Larm on GABAergic neurons (Jolas and Aghajanian, 1997). The mod- et al., 2003). GalR activation in the DRN causes a K+ conductance- ulation of 5-HT release in the DRN by κ and δ opioid receptors mediated hyperpolarization in rat brain slices (Xu et al., 1998), has also been described (Tao and Auerbach, 2002). Activation of most likely via GalR3-mediated Gi/o activation of GIRK channels δ receptors increased, while activation of κ receptors decreased 5- (Swanson et al., 2005). These effects are in agreement with in vivo HT release measured with in vivo microdialysis. The κ receptors microdialysis studies showing that injection of galanin into the effects do not involve the modulation of GABAergic or gluta- DRN reduces 5-HT release via GalR activation in the hippocampus matergic inputs in the DRN (Tao and Auerbach, 2002), suggesting (Kehr et al.,2002). In contrast to the inhibitory action of galanin on that κ receptors are expressed in 5-HT neurons. Likewise, opi- 5-HT neuronal activity, a reduction in inhibitory input onto 5-HT oid receptor-like1 (Oprl1) are most likely located and expressed neurons has also been described (Sharkey et al., 2008). Here, the in 5-HT neurons as follows. Oprl1 or nociceptin (NOP) recep- pan GalR1−3 agonist reduced GABA-mediated fast synaptic trans- tors belong to the opioid receptor family but are activated by mission accompanied by increase of PPF,suggesting that GalRs are NOP (orphanin FQ), a neuropeptide derived from prepronoci- expressed on GABAergic terminals and inhibit presynaptic Ca2+ ceptin protein. High levels of NOP receptor binding sites have channels via the Gi/o pathway. On the other hand, GalR2 agonist, been detected in the DRN (Florin et al., 2000) and Oprl1 recep- galanin (2–11) reduced IPSP amplitude but did not cause PPF,sug- tor expression could be detected in embryonic 5-HT neurons gesting a postsynaptic action (Branchek et al., 2000; Sharkey et al., (Wylie et al., 2010). NOP/orphanin FQ inhibits 5-HT release in 2008). Additionally, galanin (2–11) was demonstrated to increase the DRN via Oprl1 (Tao et al., 2007), suggesting a functional role 5-HT release in hippocampal tissue by immunofluorescence and of Oprl1 in 5-HT neurons early in development and in the adult high-performance liquid chromatography (HPLC) measurement brain.

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SUBSTANCE P addition, TRP channels have been described to be modulated by Substance P belongs to the tachykinin family and has a high D2-like receptors (Aman et al., 2007). According to the microar- affinity for the three different neurokinin receptors (NK1−3), ray expression profiling studies, various ion channel targets of in particular to NK1 (Hokfelt et al., 2001). These GPCRs cou- GPCRs are expressed in embryonic 5-HT neurons including ple mainly to the Gq/11 pathway (Stratowa et al., 1995), but TRP (Trpm4 and Trpm7), two-pore channels (TPCN1), cyclic Gs pathway activation has also been reported for NK1 in cell nucleotide gate channels (Hcn3), and KCNQ (Kcnq2; Wylie et al., culture systems (Martini et al., 2002). Various histological stud- 2010). Therefore, more detailed studies have to be performed to ies have revealed extensive expression of NK1 receptorsinthe determine the role of other ion channel targets and in particu- DRN (Maeno et al., 1993; Saffroy et al., 1994; Vigna et al., 1994; lar long-term effects of GPCR modulation for the serotonergic Charara and Parent, 1998; Sergeyev et al., 1999; Froger et al., system. 2001). Most studies suggest that NK1 receptors are not localized on 5-HT neurons (Froger et al., 2001; Santarelli et al., 2001), while others revealed NK1 receptor expression in a subpopu- INTEGRATION AND SIGNAL PROCESSING OF MODULATORY lation of 5-HT neurons (Santarelli et al., 2001; Lacoste et al., INFORMATION BY SEROTONERGIC NEURONS: WHY SO 2006, 2009). Interestingly, NK1 receptors are found in the cyto- MANY GPCRs? plasm of the 5-HT neurons and in dendritic membranes of The serotonergic transmitter system modulates many physiologi- GABAergic neurons. After administration of NK1 antagonist or cal functions such as mood, sexual behavior, feeding, sleep/wake deafferentation of substance P releasing projections, the density cycle, memory, cognition, blood pressure regulation, breath- of membrane bound NK1 receptors is increased in the soma- ing, and reproductive success (Mooney et al., 1998; Abrams et al., todendritic region of 5-HT neurons, suggesting that membrane 2004; Lechin et al., 2006; Lerch-Haner et al., 2008; McDevitt and trafficking of NK1 receptors may be regulated by Substance Neumaier, 2011). Because of the complexity and variety of the P input. This mechanism may contribute to the modulation different behaviors modulated by serotonin, it is expected that of 5-HT neuronal firing under certain physiological conditions modulatory signals from other brain areas including sensory (Lacoste et al., 2009). In addition, controversial results exist for information is integrated by GPCR signals in nuclei containing the effect of NK1 on 5-HT release and firing of 5-HT neurons. 5-HT neurons using a high diversity of GPCRs. While GABA Inhibition of NK1 in the DRN using antagonists or knock-out and glutamatergic input into the raphe nuclei will adjust 5- strategies leads to an increase in firing activity of 5-HT neu- HT neurons to the current inhibitory/excitatory state of the rons in vivo (Haddjeri and Blier, 2001; Santarelli et al., 2001). brain, other transmitter systems will inform 5-HT neurons more In contrast, activation of NK1 and NK3 increases spontaneous directly about the serotonin-associated behavior. For example, excitatory postsynaptic currents (EPSCs) in DRN 5-HT neu- dopamine is involved in reward-driven learning; ACh modu- rons resulting in an increased firing of the 5-HT neurons as lates arousal and reward; NA and CRF are involved in stress observed in brain slice recording (Liu et al., 2002a). These effects responses; histamine is involved in sleep regulation and sexual could be blocked by NK1 and NK3 antagonists (Liu et al., 2002a). function; bombesin and CCK regulate eating behavior; eCBs Also, activation of NK1 via intra-raphe injection of substance modulate memory, appetite, stress, social behavior, anxiety, and P in the DRN increases 5-HT release within the DRN, but sleep; galanin has been implicated in the regulation of sleep–wake decreases 5-HT release in frontal cortex as measured with in cycle, cognition, emotion, and blood pressure; hypocretin–orexin vivo microdialysis (Guiard et al., 2007). These effects and also modulate arousal, wakefulness, and appetite; and opioids and the described increase in 5-HT firing in NK1 knock-out mice substance P are involved in pain perception and mood (White involve changes in 5-HT1A autoreceptor levels, suggesting at least and Rumbold, 1988; Woodruff et al., 1996; Greenough et al., 1998; a functional coupling between NK1 and 5-HT1A receptors. Fur- Bear et al., 2001; Merali et al., 2006; Monti, 2010; Haj-Dahmane ther investigations to verify these interactions in 5-HT neurons are and Shen, 2011). Since all different behavioral responses can be required. integrated in nuclei containing 5-HT neurons, regulation of sero- In summary, the various heteroreceptors integrate incoming tonin release will affect similar behaviors as stated above. Thus information via two main pathways, i.e., Gi/o and Gq/11 lead- there is a tight interaction and signaling exchange between the ing to inhibition or activation of 5-HT neuronal firing and 5-HT different transmitter systems to precisely modulate behavioral out- release, respectively. Besides the “classical” Gi/o protein-mediated, put. Consequently, long-term changes in serotonin release can + membrane-delimited modulation of GIRK and presynaptic Ca2 involve changes in the auto-regulation involving 5-HT receptor channels, other ion channel targets have been identified in 5-HT or hetero-regulation involving the above mentioned GPCRs and + neurons. For example, two-pore-domain K channels [TWIK- can cause neuropsychiatric disorders, most notably depression, related acid-sensitive K-1 (TASK-1) and TASK-3] have been anxiety, schizophrenia, and dementia (Lucki, 1998; Davidson described in dorsal and caudal raphe 5-HT neurons (Washburn et al., 2000; Mann et al., 2001; Nelson and Chiavegatto, 2001). et al., 2002). TASK channels are inhibited by GPCRs coupling to The modulation of the different behaviors is even more com- the Gq/11 pathway most likely in a membrane-delimited man- plex since other GPCRs, such as orphan GPCRs, with so far ner involving the direct binding of Gαq subunits (Chen et al., unknown function are also expressed in 5-HT neurons. Therefore, 2006). The existence of voltage-sensitive but not ATP-dependent new strategies and techniques have to be applied and devel- + K channels in DRN neurons including 5-HT neurons have been oped to understand complex behaviors related to the serotonergic proposed based on drug application studies (Harsing, 2006). In system.

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NEW APPROACHES TO CONTROL AND UNDERSTAND most likely via activation of GIRK and inhibition of presynap- SEROTONERGIC G PROTEIN-COUPLED RECEPTOR tic Ca2+ channels (Li et al., 2005; Oh et al., 2010; Gutierrez et al., SIGNALING PATHWAYS 2011). Since vRh belongs to class A or rhodopsin like group of Recently, several new approaches to manipulate the activity of GPCRs, like serotonergic autoreceptors 5-HT1A/1B/1D, the idea 5-HT neurons in a cell type-specific manner have been devel- arose to generate light-activated chimeric receptors which couple oped. Various promoter/enhancer sequences have been isolated to intracellular signaling pathways in 5-HT1 receptor domains. and characterized, which allow for the expression of proteins The feasibility of receptor domain swapping has been demon- of choice within at least subsets of 5-HT neurons. These DNA strated by Dr. Khorana’s group (Kim et al., 2005). They replaced sequences include the promoter or enhancer sequences of Pet- the intracellular loops of vRh with that of the β2-adrenergic recep- 1/Fev transcription factor, the serotonin transporter (SLC6A4), tor and turned vRh into a light-activated Gs protein-coupled and the tryptophan hydroxylase 2 (TPH2; Scott et al., 2005). receptor, Opto-β2AR. The approach however was not suitable Using these different promoter/enhancer sequences, different for the exchange of vRh intracellular peptide loops by the 5- mouse lines and virus approaches have been developed to acti- HT1A intracellular receptor domains, since this chimeric receptor vate and/or silence/delete reporter genes such as green fluorescent revealed altered activation and deactivation kinetics in respect to protein (GFP) or tdTomato, Cre or Flip recombinases, tetracy- GIRK channel modulation (Oh et al., 2010). However, it could cline inducible systems, tetanus toxin light chain, and genes of be shown that the C-terminus (CT) of the 5-HT1A receptor was interest (Scott et al., 2005; Kim et al., 2009; Madisen et al., 2010, sufficient to target vRh into expression domains of 5-HT1A recep- 2012; Richardson-Jones et al., 2010; Zhao et al., 2011). Using the tor and functionally substitute for Gi/o pathway activation. The tetracycline inducible system, for example, the genetic ablation of CTs of GPCRs contain peptide signal domains for subcellular 5-HT1A from the majority of 5-HT neurons could be achieved targeting and G protein interaction. The CT of 5-HT1A had (Richardson-Jones et al., 2010, 2011). been shown to be necessary for trafficking of the receptor to For the investigation of the modulation and function of neu- dendritic domains via interaction with trafficking protein Yif1B ronal circuits in general and for the serotonergic system in (Carrel et al., 2008). Fusion of the 5-HT1A receptor CT onto particular, chemical and optogenetic techniques have been devel- vRh was therefore sufficient to target the chimeric construct Rh- oped in recent years (Herlitze and Landmesser, 2007; Masseck CT5-HT1A into somatodendritic regions of hippocampal neurons et al., 2010). For control of neuronal activity in various neuronal and 5-HT neurons in the DRN and exclude the expression of circuits including the 5-HT system, the light-gated non-selective the chimeric receptor from the axons. The Rh-CT5-HT1A receptors cation channel, ChR2 has been used and allows for the dissection were able to functionally substitute for intracellular 5-HT1A signals of 5-HT-mediated behavioral effects in different raphe nuclei (Li in DRN neurons of 5-HT1A knock-out mice, i.e., light illumi- + et al.,2005; Vargaet al.,2009; Zhao et al.,2011; Madisen et al.,2012; nation induced K conductance (most likely GIRK) reduced the see also Kim et al., 2009). For the investigation of GPCR signals, firing rate of spontaneously active 5-HT neurons. Thus, the adjust- various chemically and light-activated GPCRs have been devel- ment of for example light-activated or chemically activated GPCRs oped (Masseck et al., 2010). For example vertebrate rhodopsin and their coupling and anchoring to and in intracellular signaling (vRh) has been used to regulate Gi/o signaling pathways in neu- domains will allow for the dissection of multiple GPCR pathways rons by light (Li et al., 2005). Exogenously expressed vRh inhibits within the serotonergic system and their interaction in vitro and neuronal firing and neurotransmitter release in vitro and in vivo in vivo.

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