Chapter 10 - Serotonergic control of excitability: from neuron to networks

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Abstract

It has been known for several years that serotonin (5-hydroxytryptamine, 5-HT) acts on neuronal cell excitability in various complex organisms of the animal kingdom including humans. 5-HT stimulates a variety of 5-HT receptors which can transiently and locally alter the ion conductance in neurons, ultimately leading to change the activity of the whole neurobiological network. We have summarized here some evidence showing that 5-HT through its multiple 5-HT receptor subtypes controls the excitability of various neuronal cell populations in numerous ways. These controls evolve under various circumstances. The 5-HT modulation of excitability is more complex when we consider network level, and we have explored the meaning of this unclear notion in term of mechanisms in different organisms. Finally, we describe the 5-HT control of epilepsy which represents the extreme neuronal excitability disturbance.

Introduction

Serotonin (5-hydroxytryptamine, 5-HT) has been shown to participate in a large repertoire of behavioral responses in invertebrates and vertebrates in which it presumably plays an important role in adaptive behaviors. Although the main features of the 5-HT system impacting behaviors are quite conserved across species, its role is still puzzling. The 5-HT system acts on the excitability of neurobiological networks through multiple, overlapping, and possibly opposite mechanisms. Beyond this physiological feature, the 5-HT system could be involved in excessive excitability of neurobiological networks such as epilepsy.

The purpose of the chapter is to highlight different properties of the 5-HT system engaged in the modulation of excitability. The excitability is a complex notion with multiple levels of understanding. At the cellular/neuronal scale, it modulates the response of a cell with a depolarizing/inhibiting stimulus. This notion is often linked to the ability of a chemical to modulate ionic currents impacting on the electrical activity of the cells. The excitability of neurobiological networks is more complicated to illustrate as their ultimate responses would be the behavior itself. The 5-HT modulation of networks can be more easily studied on simple responses in vertebrates and often invertebrates. The 5-HT excitability control of neurobiological networks involved in cognition is the utmost complicated situation to deal with as these networks are likely numerous and intermingled.

The 5-HT system has the anatomical and molecular requirements to control the excitability of large cell populations. Indeed, in addition to the widespread innervation of the central nervous system (CNS), 5-HT binds to a plethora of 5-HT receptors. Apart from the 5-HT3 receptor subtype which is an ionotropic receptor, that is, ion-channel analogous to the nicotinic receptor for acetylcholine, the other 5-HT receptors are G protein–coupled receptors (GPCRs) and indirectly alter the neuronal electrical activity of different cell populations via their action to G proteins (Hoyer et al., 1994, 2002). We will illustrate such diversity by briefly mentioning their ultimate impact on neuronal activity and reporting their distribution in some neuronal cells. We will further the notion of 5-HT and excitability by showing that the impact of a given 5-HT receptor can be conditioned by its state of activation, of the basal activity of the target neurons, and more in general by the state of the neurobiological network. Therefore, it is not surprising that the 5-HT system via its receptors might exert either tonic, phasic, or constitutive modulation of different physiological functions, and this type of control can change, as causative or an epiphenomenon, in multiple pathological conditions. Here again, the distribution of 5-HT receptors at various stages of identified neurobiological networks might participate in the control of the overall input/output of the network. Finally, as an example of the complexity of 5-HT modulation in pathological conditions, we will focus on epilepsy.

In this section, we will briefly present the diversity of 5-HT receptor and their intracellular signaling pathways. Thereafter, we will address the distribution of these 5-HT receptors at the cell surface and common localization on neurons. We will then describe some 5-HT controls of neuronal excitability at cellular levels to show that it depends on various factors. 5-HT is crucial in controlling especially rhythmic electrical activity generated by neuronal network oscillations determined by a precise balance between excitation and inhibition balance (E/I balance) resulting from the coordinated activities of recurrent excitation and feedback and feedforward inhibition. Functional alterations in serotonergic functions have been associated with deficits in several pathologies such as depression, anxiety, schizophrenia, and obviously epilepsy. These pathological situations are correlated with alterations of 5-HT and its interaction with different neurotransmitter systems, such as GABA, dopamine (DA), cannabinoids (CBs), etc. that result in alterations of the E/I balance and affecting synaptic plasticity (Meunier et al., 2017).

Sixty years of 5-HT research has shown that this indolamine acts on a variety of 5-HT receptors, from the Gaddum and Picarelli’ 5-HT M and 5-HT D receptors (Gaddum & Picarelli, 1957) to the latest 14 subtypes (Hoyer et al., 2002). These receptors have been classified into seven distinct families based on their molecular composition and their pharmacological properties (from 5-HT1 to 5-HT7 receptors). Several subtypes in each family have been discovered, raising the number of distinct 5-HT receptor subtypes to 16 without counting those coming from alternative splicing (5-HT2C, 5-HT3, 5-HT4-7 receptor) and/or subjected to posttranscriptional editing (5-HT2C receptor). Textbooks indicate that 5-HT1 receptor is coupled to Gi/o, the 5-HT2 receptor to Gq, 5-HT4, 5-HT6, and 5-HT7 receptors to Gs while 5-HT6 receptor could be negatively linked to Gi/o (Fig. 10.1). In reality, the situation is much more complex due to the existence of several subtypes in each family and the ability of a given receptor to couple distinct G proteins (Raymond et al., 2001) and different G protein–independent signaling (McCorvy & Roth, 2015). We also briefly review some implications of 5-HT GPCR oligomerization. Some of these subtypes with some known intracellular signaling pathways associated with the canonical and noncanonical pathways that can play a role in the control of excitability of neuronal cells are illustrated in Fig. 10.1.

The control of the excitability of one neuron can occur at any cellular level; from the dendrites, cell bodies, axons to the terminals. There is a huge heterogeneity of neuronal location among 5-HT receptors. 5-HT1A and 5-HT1B receptors are mostly expressed in neurons of the CNS at somatodendritic and presynaptic terminals, respectively (Kia et al., 1996; Riad et al., 2000; Sari et al., 1997, 1999). As far as we know, this clear-cut distinct distribution is less evident for the other 5-HT receptors. 5-HT2C receptors would be mostly somatodendritic but strong arguments suggest that they can be addressed at terminals of some neurons (De Deurwaerdere et al., 2013; Pasqualetti et al., 1999). Examples of both distributions can be found for the other 5-HT receptors including 5-HT4 receptors (Compan et al., 1996; Vilaro et al., 2005), 5-HT6 receptors (Gerard et al., 1996, 1997), and 5-HT7 receptors (Heidmann et al., 1997; To et al., 1995; Varnas et al., 2004). In terms of resulting effect, 5-HT receptors located at proximal dendrites and soma will have a major impact on neuronal excitability in controlling synaptic efficacy (Komendantov & Ascoli, 2009).

The inhibitory impact of 5-HT1A receptor on the activity of 5-HT neurons is a typical example of the control of one 5-HT receptor on neuronal excitability. It has been initially identified by Aghajanian et al. when they observed the inhibitory effect of LSD-25 on dorsal raphe nucleus (DRN) neurons using single cell-extracellular recording technique (Aghajanian et al., 1968). It was later confirmed that this property was shared by all agents displaying a pronounced 5-HT1A receptor agonist activity and the effect was blocked by numerous 5-HT1A receptor antagonists (Blier & de Montigny, 1990b; Evrard et al., 1999; Martin et al., 1999; Sharp & Hjorth, 1990; Sprouse & Aghajanian, 1987). The activity of the 5-HT1A receptor is direct on 5-HT cells. Numerous anatomical data show that 5-HT1A receptors are autoreceptors being expressed by 5-HT neurons themselves (Gozlan et al., 1983; Miquel et al., 1994; Riad et al., 2000). The stimulation of somatodendritic 5-HT1A receptor enhances K+ conductance through G protein–gated inwardly rectifying K+ (GIRK) thereby leading to inhibitory influences (Aghajanian & Lakoski, 1984; Montalbano et al., 2015). This control appears to be phasic in nature as the administration of antagonists usually does not modulate the firing activity of 5-HT neurons (Martin et al., 1999).

Most, but not all, 5-HT neurons express 5-HT1A autoreceptors at least in mice (Kiyasova et al., 2013). Via its inhibitory effect on extracellular 5-HT in all brain regions, this receptor plays a fundamental control on the 5-HT modulation of the target area (Kreiss et al., 1993; Sharp et al., 1989; Sharp & Hjorth, 1990). As a matter of fact, the administration of 5-HT1A receptor agonists is associated with an impressive array of neuroendocrine and behavioral outcomes including a drop in body temperature, flat body posture, serotonergic syndrome, locomotor hyperactivity (Hamon et al., 1990; Lucki, 1992). Nonetheless, 5-HT1A receptors are also expressed by postsynaptic cells, notably in various cortical fields, hippocampus, amygdala, septum to name a few (Hamon et al., 1990; Kia et al., 1996; Mannoury la Cour et al., 2006; Miquel et al., 1992). These postsynaptic 5-HT1A receptors (as opposed to the somatodendritic 5-HT1A autoreceptors) would play a major role in these effects. In any case, the electrophysiological consequences and coupling efficiency toward intracellular signaling pathways are different between the two species of 5-HT1A receptor, the 5-HT1A autoreceptor coupling in majority Gαi3 (Blier & de Montigny, 1990a; Blier et al., 1993; Mannoury la Cour et al., 2006). An interesting breakthrough in the pharmacology of the 5-HT1A receptor was the synthesis of preclinical agonists to preferentially alter the activity of the somatodendritic 5-HT1A receptor (wrongly named “presynaptic”) in the raphe versus those expressed in other regions (Llado-Pelfort et al., 2010). The so-called “biased agonists” (Kenakin & Christopoulos, 2013) including F15599, which preferentially target “postsynaptic” heteroreceptors (Newman-Tancredi et al., 2009), have helped at confirming and extending specificities of the function of the distinct 5-HT1A receptors in the brain (Assie et al., 2010; Jastrzebska-Wiesek et al., 2018; van Goethem et al., 2015).

Numerous recent studies indicate that the impact of the 5-HT1A receptor on 5-HT neurons excitability evolves during the development in mammals. While it is already expressed soon after birth by 5-HT neurons, it seems unable to modulate the activity of 5-HT cells until postnatal day 21 in mice (Rood et al., 2014). This would be related to the lack of influence of the 5-HT1A receptor on GIRK, thereby participating in the higher 5-HT tone observed during the development. The link with behavior is important as it has been reported that impairment of 5-HT1A receptors during a specific time window could result in a variety of behavioral consequences including anxiety during adulthood (Donaldson et al., 2014).

The inhibitory control exerted by the 5-HT1A receptor on 5-HT neurons excitability varies after long-term treatment with pharmacological agents. The most known agents are the preferential inhibitors of 5-HT transporters (SSRI) like fluoxetine which downregulates the expression and the function of 5-HT1A autoreceptors (Evrard et al., 1999; Hamon & Blier, 2013; Le Poul et al., 1995). The chronic psychostimulant injection would also change the inhibitory control exerted by 5-HT1A receptor leading to a reinforcement of this control in case of cocaine or amphetamine (Muller et al., 2007).

To summarize, the 5-HT1A receptor plays a role in controlling neuronal excitability. This property is area-dependent, auto versus heteroreceptors, likely in relation with distinct interaction with coupling effector pathway. The control exerted by autoreceptors evolves during the development and is sensitive to various pharmacological agents.

The 5-HT1B receptors have also been found to be expressed by 5-HT neurons (Engel et al., 1986; Verge et al., 1986). At variance of 5-HT1A receptor, the 5-HT1B receptor is addressed at terminal fields of 5-HT neurons. Their impact is also inhibitory upon their stimulation on the excitability of terminal 5-HT neurons. Numerous in vitro and in vivo data provided evidence that they reduce 5-HT release and oppose excitation-induced 5-HT release (Kreiss et al., 1993; Threlfell et al., 2010). This inhibitory control of 5-HT neuron function is less known than the one attributed to 5-HT1A receptors. Like the 5-HT1A receptors, the 5-HT1B receptors are also expressed by 5-HT-receptive cells in various brain regions where they inhibit presynaptically GABA release (Bramley et al., 2005; Chadha et al., 2000; Morikawa et al., 2000).

Recent evidence indicates that the 5-HT2B receptors are expressed on 5-HT neurons and exert a positive action on the excitability of some 5-HT neurons, opposing the inhibitory influence exerted by 5-HT1A receptors (Belmer et al., 2018). The intracellular signaling pathways included a Gq transduction but have not been fully elucidated yet.

Apart from a direct control, 5-HT receptors might modulate 5-HT neurons indirectly, via interneurons. Indeed, immunoreactivity for the 5-HT2A receptors has been identified on the DRN GABAergic cells (Xie et al., 2002; Serrats et al., 2005). It should be noted that serotonergic raphe nuclei receive a prominent GABAergic input via distant sources as well as interneurons (Harandi et al., 1987; Bagdy et al., 2000; Gervasoni et al., 2000; Varga et al., 2001; Vinkers et al., 2010), and functional evidence suggests that the activation of GABA release in the DRN may be under the control of the 5-HT2A receptors (Boothman & Sharp, 2005; Quérée et al., 2009). Accordingly, in vitro studies demonstrated that the local application of the 5-HT2 agonist DOI in this brain region induces a dose-dependent increase in the frequency of inhibitory postsynaptic currents (IPSCs) (Liu et al. 2000;, Gocho et al., 2013). In vivo recordings in the DRN showed that the systemic administration of DOI attenuated the firing rate of 5-HT neurons (Wright et al., 1990; Garratt et al., 1991; Martin-Ruiz et al., 2001; Boothman et al., 2003; Boothman & Sharp, 2005; Quesseveur et al., 2013). Finally, 5-HT2C receptors are also localized on DRN GABAergic neurons but not on serotonergic neurons, and their activation induces excitation of GABAergic neurons and indirectly inhibition of 5-HT neuronal firing in vivo (Spoida et al., 2014).

Besides the autoregulation, various 5-HT receptors control neuronal excitability of all the CNS, considering the brain widespread 5-HT innervation (Hale & Lowry, 2011; Jacobs & Azmitia, 1992).

As mentioned earlier, 5-HT1A receptors can be expressed by numerous cell types other than 5-HT neurons. The coupling efficacy toward intracellular signaling pathways is different from those expressed in 5-HT neurons notably Gαo in the hippocampus or Gαi1 and Gαz in the hypothalamus (Blier & de Montigny, 1990a; Blier et al., 1993; Mannoury la Cour et al., 2006). 5-HT1A receptor stimulation reduces NMDA receptor-mediated currents in prefrontal cortex (PFC) pyramidal neurons through reduction of ERK1/2 activity, participating in the modulation of morphogenesis (Wirth et al., 2017). 5-HT1B receptors can also bind to different G proteins and β-arrestin (Marti-Solano et al., 2014; Wacker et al., 2013).

The 5-HT2C receptor has been shown to modulate the neuronal excitability of numerous neuronal populations. Rueter et al. (2000) found that the injection of currents stimulating cortical or striatal neurons needed to be enhanced in the presence of a 5-HT2C agonist and reduced in 5-HT2C receptor KO mice, suggesting an inhibitory action on striatal neurons activity (Rueter et al., 2000). In the pyramidal cells of the PFC, the 5-HT2A/C receptor inhibits rapidly maximal current amplitude linked to Na+ and amplitude of persistent Na+ current without altering its activation voltage dependence. Accordingly, the 5-HT2A/C receptor activation reduces dendritic excitability in mobilizing PLC and PKC (Carr et al., 2002). It also inhibits voltage-dependent Ca2+ channel currents, mostly Ca(v)1.2 L-type Ca2+ currents through PLC (Day et al., 2002). On the other hand, in line with its canonical coupling effector PLC, it usually enhances the firing frequency of diverse neuronal populations expressing the receptor including neurons in the substantia nigra pars reticulata (SNr) (Rick et al., 1995), the VTA GABAergic cells (Di Giovanni et al., 2001), the subthalamic nucleus (STN) (Stanford et al., 2005; Xiang et al., 2005), lateral habenula (LHb) (Delicata et al., 2018; Zuo et al., 2016), or the excitatory postsynaptic potentials (EPSPs) in pyramidal cells of hippocampus (Beck, 1992) to cite a few examples. It occurs via the reduction of K+ conductance which is still to be studied because it does not correspond to high-voltage-activated Ca2+ channel currents, calcium-dependent potassium currents, and afterhyperpolarization cAMP ion gated K+ channels (Xiang et al., 2005). There are other neuronal populations for which the understanding of the impact of the 5-HT2C receptor is less clear and notably dopaminergic (DAergic) neurons. It was previously shown that nonselective 5-HT2C antagonists enhanced the excitability of DAergic neurons, implicitly suggesting that 5-HT2C receptor stimulation reduces DAergic neurons excitability (Prisco et al., 1994; Trent & Tepper, 1991). A subpopulation of DAergic neurons (∼30%) express 5-HT2C receptors (Bubar & Cunningham, 2007; Bubar et al., 2011; Valencia-Torres et al., 2017; Xu et al., 2017), which seem to mediate effects of 5-HT drugs in inhibiting binge-like eating and directly excited by 5-HT and 5-HT2C receptor agonist such as lorcaserin in vitro (Xu et al., 2017). Nevertheless, activation of the 5-HT2C receptors would indirectly inhibit VTA DAergic activity via local GABAergic interneurons (Di Giovanni & De Deurwaerdere, 2016; Di Giovanni et al., 2001; Valencia-Torres et al., 2017). To increase the level of complexity of this modulation, 5-HT2C receptors might control DA neurons via the nucleus accumbens (NAc)/striatum complex (Di Giovanni & De Deurwaerdere, 2016). The 5-HT2A receptors could also participate in some of the reported effects. Usually, they enhance neuronal activity by reducing afterhyperpolarization-activated currents (Ih) (Celada et al., 2013). The 5-HT4 receptors have been shown to enhance the excitability of neurons in the STN (Stanford et al., 2005; Xiang et al., 2005), the cortex (Cai et al., 2002), the hippocampus (Torres et al., 1995), and the globus pallidus (GP) (Chen et al., 2008) in virtually all studies with some specificities. It could occur via the inhibition of the AHP currents and/or cAMP elevation, perhaps independent from protein Kinase A (PKA) and Ih (Chapin et al., 2002) and involve a Ba2+-sensitive inwardly rectifying K+ current (Mlinar et al., 2006).

The 5-HT6 receptor may likely alter the electrical activity of various neuronal populations, but it has not been the object of numerous studies. In fact, it has been reported an indirect action of 5-HT6 receptor on the activity of midbrain DAergic neurons (Borsini et al., 2015) or 5-HT neurons (Brouard et al., 2015).

The 5-HT7 receptor can also enhance neuronal excitability as reported in the GP (Chen et al., 2008), the cortex (Beique et al., 2004), the hippocampus (Tokarski et al., 2003), and in the dorsal root ganglions (Cardenas et al., 1999). At variance with 5-HT4 receptors, this facilitation involves the inhibition of Ih involving the rise of cAMP and PKA activation (Cardenas et al., 1999; Chen et al., 2008; Tokarski et al., 2003).

There are examples of interaction between 5-HT receptors in the control of excitability of neuronal cells (Celada et al., 2013). It is dependent on the age of the animal, as reported for the inhibitory control of the 5-HT1A receptor on DRN 5-HT neurons, or in the developing cortex as regards the 5-HT1A-2A-7 receptors (Beique et al., 2004) or hippocampus (Kobe et al., 2012). It is, thus, difficult to predict the resulting effects produced by the concomitant stimulation of the several 5-HT receptors upon neurons. It is also dependent on the state activity of the cell, which is a critical point when addressing the control exerted by 5-HT receptors upon the excitability of an entire neural network. For instance, the 5-HT4 receptor can facilitate or decrease the GABA-evoked currents in PFC neurons through PKA and this mechanism would be dependent on the basal activity of PKA (Cai et al., 2002). The status of the activity is probably the main actor in the control of excitability.

Since some 5-HT receptors can be expressed in the same cell, there might also be some physical interactions between these receptors. Indeed, a growing number of experimental evidence suggests that 5-HT receptors homo- and heterodimerize and a number of heterodimerizations/combinations have been shown (Herrick-Davis et al., 2005; Teitler & Herrick-Davis, 2014). It is possible that, depending on their final addressing in the cell, heterodimerization could play a role in 5-HT neurotransmission (Herrick-Davis, 2013). This has been suggested by recent functional data with 5-HT2A and 5-HT2C receptors using exogenous molecular targeting (Anastasio et al., 2015; Moutkine et al., 2017). Since it should not occur in brain regions where these receptors are not expressed by the same cells such as the habenula (Delicata et al., 2018), this phenomenon would be, again, area-dependent.

The controls of neuronal excitability by 5-HT can be multiple not only through the involvement of the different subtypes but also on numerous additional factors (Fig. 10.2).

The 5-HT innervation arising from the cell bodies located in the raphe nuclei to the CNS is widely diffused. The organization of cell projection from the DRN indicates some specificity as regards the projection areas (Hale & Lowry, 2011; Kiyasova et al., 2013; Niederkofler et al., 2016). Regardless of this anatomical diversity, it means that 5-HT can affect different neurobiological networks and their interaction. A neurobiological network corresponds to a set of neurons or even a set of cerebral structures involved in an identified function. The distribution of 5-HT receptors has been quite well studied in mammals (Barnes & Sharp, 1999; De Deurwaerdere & Di Giovanni, 2017) although there are still some regions poorly investigated (Di Giovanni et al., 2018). Each subtype has its own distribution, marked by higher densities in some networks compared to others. For instance, 5-HT1A receptors are more expressed in limbic regions, whereas 5-HT2A receptors are highly expressed in cortical areas. 5-HT1B, 5-HT4, or 5-HT6 receptors are densely expressed in the basal ganglia compared to some other regions (Barnes & Sharp, 1999; De Deurwaerdere & Di Giovanni, 2017; Roberts et al., 2002; Sari et al., 1997; Vilaro et al., 2005). In all cases, in vertebrates and invertebrates, several 5-HT receptors are expressed in a given neurobiological network. It confers to 5-HT the property to shape the functional organization of the networks and ultimately the behavioral responses associated with them.

An exemplifying scenario is 5-HT modulation of the activity of lateral giant neurons of crayfish. These neurons are the command for a tailflip escape behavior associated with the fight and the inherent acquisition of social status between congeners. The action of exogenous application of 5-HT on afferent synaptic differences to this command differs according to the social experience. It enhanced and inhibited the response of lateral giant neurons triggered by sensory stimuli in socially dominant and subordinate crayfish, respectively (Yeh et al., 1996). Whereas these actions were reversible, the authors further showed that the response was persistently inhibited in isolated crayfish (Yeh et al., 1996). The inhibitory response to 5-HT was found to be lost and changed toward an excitation in a subordinate winning a fight against another subordinate. On the other hand, 5-HT still enhanced the response of the lateral giant neurons in socially dominant crayfish even after subsequently lost fights (Yeh et al., 1997). Physiologically, it has been reported in lobsters that lateral giant neurons activation could elicit EPSPs in 5-HT cells, suggesting that the network correspondingly acts on the neuromodulatory 5-HT tone (Horner et al., 1997). The way it could act on the 5-HT tone is probably important because the application of exogenous 5-HT at low or gradually increasing high concentrations facilitates the tailflip escape response in crayfish. The fast application of high concentrations of exogenous 5-HT conversely inhibited the tailflip response (Teshiba et al., 2001). The effect of 5-HT can persist for hours if the application is prolonged (Teshiba et al., 2001). The pleiotropic behavior of 5-HT for the facilitation is due to different influences in the network promoting either a more efficient electrical coupling between mechanoreceptors and lateral giant neurons, an increase in the membrane resistance of dendrites of lateral giant neurons, and an increase in input resistance of lateral giant neurons near the initial segment (Antonsen & Edwards, 2007). The depression of synaptic inputs by 5-HT involves other mechanisms that are independent of PKA, although PKA can be involved in depressed responses (Lee et al., 2008). Even though the 5-HT receptors in crayfish have been less characterized, it has been shown that the various responses of 5-HT involved several distinct 5-HT receptors (Edwards & Spitzer, 2006; Yeh et al., 1996, 1997).

The neuromodulatory influence of 5-HT modifies the response of the network with the experience. In mammals, it is extremely complicated to precisely determine the different contributions of 5-HT mechanisms in the control of neurobiological networks. As regards cognition and decision-making, 5-HT participates in the modulation of the cortico-cortical and cortico-subcortical loops at all stages (Dalley et al., 2008, 2011). A specific pattern of 5-HT neuron alterations is still difficult to understand in a behavioral dimension such as impulsivity (Bari & Robbins, 2013; Dellu-Hagedorn et al., 2018). It is often assumed that 5-HT tone is decreased in depressed patients but the data would also support an excessive tone in melancholia, for instance (Andrews et al., 2015). Thus, it is difficult to generalize a pattern of changes of 5-HT system markers for a specific symptom in a multifactorial pathology. 5-HT neurons likely shape brain connectivity and it occurs via its multiple 5-HT receptors located in different places in the brain and cells (Lesch & Waider, 2012).

In invertebrates, a number of data has reported a role of 5-HT in the control of small networks. The pyloric network of the spiny lobster stomatogastric ganglion is considered as a model central pattern generator. The composition of the neurons encompassing the network has been well characterized and is sensitive to modulatory influences of biogenic amines including 5-HT. At the graded synapse from the pyloric dilator neuron to the lateral pyloric neuron in a form of depressed response of the system, 5-HT reduced graded IPSP magnitude, increased the amount of synaptic depression, and accelerated the onset of depression (Kvarta et al., 2012). The existence of multiple effects is compatible with the pharmacological identification of several 5-HT receptors. Each receptor alters in a distinct manner the function of the stomatogastric ganglion. A 5-HT3 receptor inhibited the pyloric constrictor neurons. A 5-HT2 receptor induced rhythmic bursting in the electrically coupled anterior burster and pyloric dilator neurons. Another 5-HT2 receptor induced tonic excitation of the lateral pyloric neuron (Zhang & Harris-Warrick, 1994). Interestingly, it has been reported that one of them, identified as the arthropod 5-HT2βPan receptor, was expressed in the fine neurites of pyloric neurons and could modulate firing properties and/or synaptic efficacies. This specific receptor exhibits a constitutive activity impacting the activity of pyloric neurons (Clark et al., 2004).

In mammals, the 5-HT2C receptor has been proposed to play an inhibitory control of brain network excitability (Tecott et al., 1995). This idea came from the finding that 5-HT2C receptor KO mice were prone to develop epilepsy (see below). The 5-HT2C receptors are also expressed in the cortex and the basal ganglia, the latter group of subcortical regions being involved in the control of motor behavior. While they are present in all brain regions including the striatum and the NAc, the SN and the GP pars interna (GPi) and externa (GPe), the resulting effects upon the peripheral injection of an agonist in each brain region is distinct according to the brain region considered (De Deurwaerdere et al., 2013). They preferentially act on the activity of the two cortical entries of the basal ganglia, namely the striatum and the STN. The integrative properties of the basal ganglia are enhanced by 5-HT2C receptor stimulation, either by enhancing the impact of cortical inputs or by unmasking the cortical impact (Beyeler et al., 2010; Lagière et al., 2018) (Fig. 10.3). The influence of the 5-HT2C receptor in output regions of the basal ganglia is more complicated. For instance, Kita et al. (2007) raised the concern that despite the fact that 5-HT2C receptors were present in the GPi, the stimulation of pallidal 5-HT2C receptors was surprisingly devoid of effect (Kita et al., 2007). The ability of 5-HT2C receptor to modulate neuronal excitability in the internal pallidum is indeed low (Navailles et al., 2013) and would be dependent on the state of activity of the network, often in line with the consequences of long-term DAergic tone changes (Graves et al., 2013; Lagiere et al., 2013). Therefore, the expression of the same 5-HT receptors by different neurobiological networks that interact may lead to opposite or distinct behavioral responses. For instance, the stimulation of 5-HT2C receptors would dampen impulsive responses and conversely promote compulsive responses (Anastasio et al., 2015; Da Cunha et al., 2015; Di Giovanni & De Deurwaerdere, 2016; Higgins et al., 2016; Kreiss & De Deurwaerdere, 2017; Winstanley et al., 2004). Based on this construct, it is not so surprising that both agonists and antagonists at 5-HT2C receptors have been proposed in the treatment of mood disorders (Di Giovanni & De Deurwaerdere, 2016).

The higher level of complexity is due to the involvement of several 5-HT receptors in intermingled neurobiological networks. It has been the object of an interesting review reporting the expression of various 5-HT receptors in the ability of the 5-HT system to shape brain connectivity (Lesch & Waider, 2012). The authors recall the dynamics of 5-HT receptors in the developing brain through an impact on synaptogenesis and morphology (Lesch & Waider, 2012; Wirth et al., 2017).

The state-dependent influence of 5-HT receptor has been well exemplified in the control of nigrostriatal and mesolimbic DAergic neurons. While endogenous 5-HT barely inhibits the electrical activity of DA neurons without consequences on DA extracellular levels, the changes of activity of DAergic neurons promote the activation of a variety of 5-HT receptors according to the situation. It is likely that these effects operate as a consequence of the change of neural networks dynamics in basal ganglia as most 5-HT receptors would not be expressed by DAergic neurons (De Deurwaerdere & Di Giovanni, 2017; Di Giovanni & De Deurwaerdere, 2016; Di Giovanni et al., 2008a).

5-HT neurons display a tonic activity of discharge which is low compared to other neuronal systems (0.5–2 Hz). In addition to a presumed presynaptic release, 5-HT is always present at very low concentrations in the extracellular space. These concentrations could be sufficient in maintaining a 5-HT tone on 5-HT receptive cells via 5-HT receptors displaying the highest affinity for 5-HT (e.g., 5-HT2C receptors). Tonic controls have been postulated at many occasions, in particular, in the control exerted by 5-HT on DAergic neuron activity (De Deurwaerdere & Di Giovanni, 2017; Di Giovanni et al., 2008b).

Most 5-HT receptors are supposed to be recruited in phasic conditions. The phasic conditions imply responses to stimuli and could correspond to (1) a change of activity of 5-HT neuron activity/release and (2) a change of activity of the cell expressing the 5-HT receptors. There is a particular case when 5-HT receptors display a constitutive activity, an activity of the receptor that is independent on the presence of the agonist (Kenakin, 2001; Milligan et al., 1995). Their impact would be phasic in nature rather than tonic, that is, the impact depends on the activity of the cell expressing the receptor.

The constitutive activity of some 5-HT receptors has been proposed to participate in the control of networks activity. It is a complicated task to firmly isolate constitutive activity of a given receptor because it requires a meticulous use of diverse classes of pharmacological ligands, the most selective ones (Navailles & De Deurwaerdère, 2010). 5-HT2C receptors likely display a constitutive activity in the basal ganglia impacting at least the release of DA in the striatum and the NAc (De Deurwaerdere et al., 2004). It also modifies other parameters, but it is more complicated in mammals to determine if this activity directly alters neuronal excitability in the network compared to other networks like the one described in lobster. The constitutive activity would be more related to a 5-HT2C receptor located in the striatum/NAc and in the PFC (Di Giovanni & De Deurwaerdere, 2016). It can also be triggered in humans by spinal cord lesion, leading to an abnormal spasm response sustained by the aberrant constitutive activity of 5-HT2C receptors directly impacting the excitability of spinal networks (Murray et al., 2011). The 5-HT2B receptors (Fouad et al., 2010; Murray et al., 2011) and 5-HT4 receptors (Keating & Spencer, 2018) have been proposed to have a constitutive activity under specific circumstances and in specific tissues. The situation for the 5-HT2A receptors or the 5-HT1B receptors is still unclear and is based essentially on behavioral data (De Deurwaerdère et al., 2018; Millan et al., 1999). The other 5-HT receptors, 5-HT4, 5-HT6, and 5-HT7 receptors, can presumably adopt an active form without 5-HT but the functional evidence is lacking in vivo.

As we have highlighted in the previous sections, 5-HT is an important neurotransmitter in the brain as it is involved in many neurological and psychiatric diseases including epilepsy.

Serotonin receptors may directly or indirectly depolarize or hyperpolarize neurons by changing the ionic conductance and/or concentration within the cells (Barnes & Sharp, 1999). It is thus not surprising that 5-HT is able to change the excitability in most networks involved in epilepsy (Bagdy et al., 2007; Jakus & Bagdy, 2011). Moreover, a common 5-HT dysfunction might underlie both epilepsy and comorbid depression seen in people with epilepsy (Guiard & Di Giovanni, 2015; Kanner et al., 2012).

The involvement of the 5-HT system in epilepsy was suggested in the late 1950s (Bonnycastle et al., 1957). Furthermore, 5-HT is known to regulate a wide variety of focal and generalized seizures, including absence epilepsy both in human and in animal models (Bagdy et al., 2007; Favale et al., 2003; Guiard & Di Giovanni, 2015; Jakus & Bagdy, 2011; Lorincz et al., 2007). In general, agents that elevate extracellular 5-HT levels, such as 5-hydroxytryptophan and 5-HT reuptake blockers, inhibit both focal (limbic) and generalized seizures (Prendiville & Gale, 1993; Yan et al., 1994). Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically, and electrically evoked convulsions (Statnick et al., 1996). More recently, an increased threshold to kainic acid–induced seizures was observed in mice with genetically increased 5-HT levels (Tripathi et al., 2008). These findings are corroborated by data showing mice lacking the 5-HT1A (Parsons et al., 2001; Sarnyai et al., 2000), 5-HT2C (Applegate & Tecott, 1998), 5-HT4 (Compan et al., 2004), and 5-HT7 receptors (Witkin et al., 2007). Also, rats knocked down for the 5-HT2A receptors by antisense oligonucleotide treatment (Van Oekelen et al., 2003) are extremely susceptible to chemical- and electrical-induced seizures. Nevertheless, only 5-HT2C receptor KO mice are prone to spontaneous death from seizures (Tecott et al., 1995). In addition, seizures have not been reported with pharmacological blockade of different 5-HT receptors. It is possible that adaptive changes involving different mechanisms may play a role in the low seizure thresholds observed in 5-HT receptor KO mice. In general, therefore, it seems that 5-HT neurotransmission by activating different 5-HT receptors suppresses neuronal network hyperexcitability and seizure activity (Bagdy et al., 2007), although opposite effects have also been reported, especially for 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors (Gharedaghi et al., 2014).

The role of pharmacological activation of 5-HT2A receptors in epilepsy modulation is far from being well established. However it might be an important potential target in the light of recent evidence that their activation might not only be anticonvulsant but also capable of reducing seizure-related mortality due to sudden unexpected death in epilepsy (SUDEP) (Buchanan et al., 2014), the leading cause of death in patients with refractory epilepsy (Shorvon & Tomson, 2011). The 5-HT2A receptor agonists have been described to be both pro- and anticonvulsants. This might essentially be due to (1) the high degree of genetic, pharmacology, and signal transduction pathways homology of the 5-HT2 receptor family (Di Giovanni et al., 2006; Higgins et al., 2013), (2) the diversity among epilepsy experimental models, and (3) the different animal strains used. For instance, DOI strongly facilitated kindling development and reduced the number of stimulations needed to produce generalized seizures in the amygdaloid kindled rats (Wada et al., 1997). DOI was ineffective in any parameters on hippocampal partial seizures generated by low-frequency electrical stimulation of the hippocampus in rats (Watanabe et al., 1998). Similarly, Wada and colleagues showed that in the feline hippocampal-kindled seizures DOI had no effect (Wada et al., 1992). In the same model, the selective 5-HT2A antagonist MDL100907 had no effect on seizure thresholds, secondary AD duration, or latency of secondary AD (Watanabe et al., 2000). In other experimental models, 5-HT2A receptor antagonists have failed to be effective in seizure control. The 5-HT2A/2C receptor antagonist ritanserin was ineffective on kainic acid–induced seizures (Velisek et al., 1994). The more selective 5-HT2A receptor antagonist ketanserin did not affect the seizure threshold for picrotoxin in mice (Pericic et al., 2005) or on ethanol withdrawal seizures (Grant et al., 1994), but antagonized cocaine-induced convulsions in a dose-dependent manner (Ritz & George, 1997). The 5-HT2A/2C receptor and calcium antagonist dotarizine inhibited electroconvulsive shock-induced seizures but had no effect on PTZ-induced convulsions in rats (Lazarova et al., 1995). On the other hand, 5-HT2C receptors seem devoid of any modulatory role in partial seizures or paradoxically instead have a proepileptic one in this type of epilepsy. Indeed, we showed that mCPP and lorcaserin, but not RO60-0175 were able to halt hippocampal afterdischarges in a rat model of temporal lobe epilepsy (TLE), an effect potentiated and not blocked by pretreatment of SB 242,084 (Orban et al., 2014). These data indicate that other 5-HT receptors are involved in the antiepileptic effect of mCPP and lorcaserin, probably the 5-HT1A/7, 5-HT2A/2B receptors (Orban et al., 2013) or unknown targets, confirming previous findings (Damjanoska et al., 2003; Navailles et al., 2013; Orban et al., 2014). Moreover, we have further confirmed a proepileptic role of 5-HT2C receptors in the pilocarpine-induced status epilepticus model, in which the anticonvulsant effect of combined administration of Ro60-0175 and the CB1/2 receptor agonist WIN55,212-2 is not blocked either by SB242084 or the 5-HT2A receptor agonist MDL11,903. Conversely, the antiepileptic effect was blocked by the 5-HT2B receptor antagonist RS127445, but 5-HT2B receptor activation by Ro60-0175 did not produce any effect (Colangeli et al., 2019). In agreement to this evidence, the 5-HT2B receptor agonist BW-723C86 had no effect on the threshold for generalized seizures in PTZ and electroshock-evoked seizures in mice and rats (Upton et al., 1998).

As far as the 5-HT control of generalized absence seizures (ASs) is concerned, 5-HT1A–2C and 5-HT7 receptors have been studied in the expression of this form of epilepsy in Wistar Albino Glaxo/Rij rat (WAG/Rij) (Bagdy et al., 2007) and in Genetic Absence Epilepsy Rat from Strasbourg (GAERS) (Venzi et al., 2016). Briefly, activation or inhibition of 5-HT1A and 5-HT7 receptors increases or decreases ASs, respectively, while 5-HT2C receptor agonists are effective in inhibiting epileptiform activity and 5-HT2C receptor antagonism lacks any effects (Jakus & Bagdy, 2011; Jakus et al., 2003). In agreement with this evidence, fluoxetine and citalopram caused a moderate increase in spike and wave discharges (SWDs); potentiated or inhibited by pretreatment with SB-242,084 and the 5-HT1A receptor antagonist WAY-100,635, respectively (Jakus & Bagdy, 2011). We recently showed that in GAERS, Ro60-0175 (unpublished observation), lorcaserin, and CP809,101 were capable of blocking SWDs (Venzi et al., 2016). SB 242,084 not only blocked the effect of lorcaserin and CP809,101 but also showed some antiabsence effects. In another genetic animal model of absence epilepsy, the Groggy (GRY) rats, increasing 5-HT levels by treatment with the 5-HT reuptake inhibitors fluoxetine and clomipramine, inhibit SWD generation, an effect mimicked by DOI and blocked by ritanserin pretreatment (Ohno et al., 2010). Consistently, in atypical ASs induced by AY-9944, DOI reduced the total duration and number of SWDs, and ketanserin exacerbated the number of SWDs. In contrast to the evidence obtained in WAG/Rij rats, 5-HT2C receptor activation by mCPP had no effect on total duration or number of SWD in this model of atypical absence epilepsy (Bercovici et al., 2007).

Since we have recently shown that the neurons of the ventrobasal thalamus (VB) have an aberrant extrasynaptic GABAA (eGABA) current and that this is a necessary factor in the expression of SWDs associated with typical absence epilepsy (Cope et al., 2005; Di Giovanni et al., 2011; Errington et al., 2011, 2014), it is conceivable that some of the systemically injected 5-HT ligand effects on ASs (Bagdy et al., 2007; Bercovici et al., 2007; Danober et al., 1998; Isaac, 2005; Ohno et al., 2010; Venzi et al., 2016) occur via a modulation of tonic eGABAA inhibition. This hypothesis is supported also by the evidence that DA and especially the activation of D2 receptors decreases both ASs (Deransart et al., 2000) and eGABAA current in GAERS VB neurons (Crunelli & Di Giovanni, 2014; Yague et al., 2013). Indeed, our preliminary results show that the 5-HT2A and 5-HT2C receptor activation significantly decreased the tonic eGABAA conductance in TC VB neurons of GAERS rats. From these findings, we can speculate that the activation of the 5-HT2A/2C receptors in the VB and a contextual decrease of GABAA receptor tonic inhibition would be responsible for 5-HT2A and 5-HT2C receptor agonist antiepileptic activity, although this evidence needs to be tested in vivo (Fig. 10.4).

As far as the pathophysiological mechanisms of ASs are concerned, invasive experimental work (Williams, 1953) and more recent noninvasive imaging studies in humans (Bai et al., 2010; Hamandi et al., 2006; Holmes et al., 2004) have indicated that these seizures are generated by paroxysmal electrical activity of cortical and thalamic networks. In particular, studies in mouse and rat genetic absence models have shown that SWDs initiate in somatosensory cortex, from where they rapidly spread to other cortical areas and to the thalamus. The presence of a cortical “initiation site” for SWDs of ASs has now been conclusively demonstrated in CAE and other patients with ASs, challenging the classical view of SWD as a fully generalized EEG paroxysm, at least at its onset.

The main activity of layer V/VI cortical neurons during SWDs are rhythmic depolarizations that occur in phase with the EEG spike, and whose waveform is drastically different from the classical paroxysmal depolarizing shifts of convulsive epilepsies. Possible candidates for cortical abnormalities underlying the expression of this firing pattern may include an increased NMDA-mediated excitation in deep layers, a decreased GABAergic inhibition in layer II/III, and/or abnormalities in HCN channels. In NRT neurons in vivo, the enhanced and more synchronous cortical volley of SWDs, together with the convergence of the corticothalamic input, results in bursts of EPSPs, that at times generate a T-type Ca2+ channel-dependent high-frequency burst of action potentials in correspondence to each spike of the SWD. Alterations in GABA-A γ2 subunits, T-type Ca2+ channels, gap–junction coupling, and/or excitatory and inhibitory synaptic strengths have been suggested to occur in the NRT of genetic absence models. The strong and prolonged inhibitory output of the NRT, coupled to the deficient GABA transporter-1, lead TC neurons to the presence of rhythmic sequences of four to six GABAA IPSPs and a marked increase in tonic eGABAA inhibition. Thus, the firing rate of these thalamic neurons during ASs decreases and only occasional action potentials are observed in synchrony with the spike component of SWDs. Notwithstanding, there is always a synchronized output from thalamus to cortex during ASs (McCafferty et al., 2018). 5-HT via its receptors is known to modulate the corticothalamic network affecting states of conscience and vigilance (arousal attention and sleep) and higher-level cognitive processes (Jacobs & Fornal, 2000).

5-HT2A/2C receptors are widely expressed in the corticothalamic network and in areas known to be involved in the modulation of SWDs, that is, the striatum, NAc, and the SNr (Depaulis et al., 2016). At the cellular level, 5-HT2A receptors are expressed by different cortical neurons, mainly by pyramidal neurons of layer V (but also II and III) (Jakab & Goldman-Rakic, 1998; Willins et al., 1997), by different classes of interneurons, and presynaptically by thalamiccortical fibers and glial cells (Cornea-Hébert et al., 1999; Miner et al., 2003; Xu & Pandey, 2000). Apart from expressing 5-HT2A receptors at the level of its cortical terminals, TC VB neurons might express 5-HT2A receptor immunoreactivity at the level of the soma since they contain the mRNA (Cornea-Hébert et al., 1999; Cyr et al., 2000). However, the presence and exact pre- versus postsynaptic cellular localization of 5-HT2 receptors within the VB is yet unknown. 5-HT2C receptors are expressed in thalamocortical (TC) neurons in the dorsal lateral geniculate nucleus (dLGN) (Coulon et al., 2010). GABAergic interneurons of the dLGN contain 5-HT2C receptor mRNA, and their activation induces an increase of phasic GABAA receptor inhibition in dLGN TC neurons in mice (Munsch et al., 2003). The intracellular pathways that couple the 5-HT2 receptors to the Ca2+-influx mechanism depend on the PLC system and the transient receptor potential (TRP) protein TRPC4 (Munsch et al., 2003).

5-HT in the thalamus induces depolarization of TC neurons and changes in their firing pattern from burst to single spike activity (McCormick, 1992). 5-HT induces membrane depolarization by inhibition of a leak K+ conductance (Meuth et al., 2006) and Ih (Chapin & Andrade, 2001; Pape & McCormick, 1989). The 5-HT2C receptor agonist CP809,101 and 5-HT produce similar depolarization effects activating Gq protein (Coulon et al., 2010). Ketanserin, a 5-HT2A/2C receptor antagonist, was capable of blocking 5-HT-induced switch in the NRT neuronal pattern activity. Therefore, 5-HT modulation of sleep–waking activity might depend on GABAergic neurons of the NRT (McCormick & Pape, 1990; McCormick & Wang, 1991).

5-HT promotes waking and suppresses REM sleep but on the other hand, 5-HT2C receptor KO mice have an increase of waking and a reduction in nonrapid eye movement (NREM) sleep. Different results come from pharmacological experiments where selective 5-HT2C antagonists and nonselective 5-HT2A/2C antagonists increase slow wave sleep (SWS) and reduce REM sleep, respectively (Popa et al., 2005). On the other hand, nonselective 5-HT2A/2C agonists and selective 5-HT2C agonists increased waking and reduced SWS and REM sleep.

During ictal activity recorded in animal models of absence epilepsy, TC neurons are generally silent (McCafferty et al., 2018; Pinault et al., 1998; Polack et al., 2007) due to an increased corticothalamic excitatory input into NRT neurons compared to TC neurons. We hypothesize that during ASs, 5-HT2A/2C receptor agonists have antiabsence effects by decreasing GABA release form NRT neurons into VB TC neurons leading to a reduced GABAA phasic and tonic current. Nevertheless, that it is not impossible that 5-HT2C receptors have both anti- and proepileptic effects, depending on which brain area population is activated. For example, in the cortex, 5-HT2C receptors are both highly expressed on inhibitory interneurons (Liu et al., 2007) and pyramidal cortical neurons. The 5-HT2C receptor activation may also induce an increase of thalamic glutamate release (Puig et al., 2003) (Fig. 10.4).

Another potential way by which 5-HT2C receptors modulate ASs may be through other neurotransmitters such as DA, and noradrenaline known to modulate the arousal state and thalamic and cortical pathological oscillations seen in absence epilepsy (Di Giovanni, 2013; Di Giovanni et al., 2008b, 2010).

Section snippets

Conclusions

The 5-HT repertory of action on neuronal activity is impressive in part due to the multiplicity of 5-HT receptors incremented by their ability to couple distinct intracellular signaling pathways. The final specificity is tissue dependent and evolves with the maturation of the neuron interacting in a neurobiological pathway. 5-HT is neither strictly inhibitory nor excitatory in a neurobiological network. Indeed, the same receptor can be expressed at different places of the circuits leading to

Acknowledgments

Our research reviewed here was supported in part by Malta Council of Science and Technology, grant R&I-2013-14 EPILEFREE to GDG. PDD acknowledges the Centre National de la Recherche Scientifique for its support.

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