Histamine in brain development - Wiley Online Library

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GABA, c-aminobutyric acid; H1Rs, histamine H1 receptors; H2Rs, histamine H2 receptors; H3Rs, histamine H3 receptors; H4Rs, histamine. H4 receptors; HA ...


| 2012 | 122 | 872–882

doi: 10.1111/j.1471-4159.2012.07863.x

*Departamento de Biologı´a Celular, Instituto Nacional de Perinatologı´a Isidro Espinosa de los Reyes, Me´xico, D.F., Me´xico  Departamento de Fisiologı´a, Biofı´sica y Neurociencias, Centro de Investigacio´n y de Estudios Avanzados del IPN, Me´xico, D.F., Me´xico

Abstract The function of histamine in the adult central nervous system has been extensively studied, but data on its actions upon the developing nervous system are still scarce. Herein, we review the available information regarding the possible role for histamine in brain development. Some relevant findings are the existence of a transient histaminergic neuronal system during brain development, which includes serotonergic neurons in the midbrain and the rhombencephalon that coexpress histamine; the high levels of histamine found in several areas of the embryo nervous

system at the neurogenic stage; the presence of histaminergic fibers and the expression of histamine receptors in various areas of the developing brain; and the neurogenic and proliferative effects on neural stem cells following histamine H1- and H2-receptor activation, respectively. Altogether, the reviewed information supports a significant role for histamine in brain development and the need for further research in this field. Keywords: central nervous system, development, histamine, histamine receptors, neural stem cell. J. Neurochem. (2012) 122, 872–882.

Histamine (HA) is a neurotransmitter in the adult mammalian CNS, where it regulates via both pre- and post-synaptic mechanisms a variety of central responses and functions, such as wakefulness, feeding, drinking, the neuroendocrine system, body temperature, analgesia and motor activity. Histaminergic (HAergic) neurons are located in the hypothalamic tuberomamillary nucleus from where they send diffuse projections to almost all brain regions (Wada et al. 1991a; Haas and Panula 2003). These neurons are grouped into five clusters denominated E1–E5 (Wada et al. 1991b; Haas et al. 2008), bridged by scattered neurons, and with each group sending overlapping projections throughout the neuroaxis with a low level of topographical organization. Histaminergic neurons present functional heterogeneity as evidenced by their response to stress, glycine, c-aminobutyric acid (GABA), and antagonists/inverse agonists at H3 autoreceptors. For example, the intrahypothalamic perfusion of bicuculline, an antagonist at GABAA receptors that acts directly onto histaminergic neurons to augment cell firing, increased histamine release in the tuberomamillary nucleus, nucleus accumbens, and prefrontal cortex, but not in striatum. Likewise, H3-receptor (H3R) antagonists/inverse agonists, such as thioperamide and GSK-189254, augmented histamine release in the tuberomamillary nucleus, prefrontal cortex, and

nucleus basalis magnocellularis, but not in nucleus accumbens or striatum. This evidence suggests that the histaminergic system is organized into distinct pathways modulated by selective mechanisms, implying independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections (Blandina et al. 2012). Three (H1, H2, and H3) of the four histamine receptors characterized to date by their molecular and pharmacological properties are widely expressed in the nervous system (Haas and Panula 2003; Haas et al. 2008; Leurs et al. 2009). The neuronal expression of H4 receptors (H4Rs) has also been reported and their specific functions have begun to be studied (Connelly et al. 2009; Ferreira et al. 2012). All four


Received May 24, 2012; revised manuscript received July 2, 2012; accepted July 3, 2012. Address correspondence and reprint requests to Dr. Anayansi MolinaHerna´ndez, Departamento de Biologı´a Celular, Instituto Nacional de Perinatologı´a, Montes Urales 800, Torre de Investigacio´n, 11000 Me´xico, D.F., Me´xico. E-mail [email protected] Abbreviations used: cAMP, 3¢-5¢-cyclic adenosine monophosphate; GABA, c-aminobutyric acid; H1Rs, histamine H1 receptors; H2Rs, histamine H2 receptors; H3Rs, histamine H3 receptors; H4Rs, histamine H4 receptors; HA, histamine; NSCs, neural stem cells.

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histamine receptors belong to the rhodopsin-like family of G protein-coupled receptors (Hill et al. 2012). For rat embryonic development, HA is one of the first neurotransmitters to be present in the CNS, reaching its maximum level at embryo days (E) 14–16 to steadily decrease until birth, yielding at E20 the concentration present in the adult organism (Vanhala et al. 1994). This level peak coincides with the period where neuronal differentiation takes place in several brain regions (Sauvageot and Stiles 2002; Gotz and Huttner 2005), suggesting that HA, acting as a trophic and/or neurogenic factor, is an important modulator in the developing brain (Molina-Hernandez and Velasco 2008; Rodrı´guez-Martı´nez et al. 2012) (Fig. 1). Furthermore, histidine decarboxylase, the enzyme that synthesizes HA from L-histidine, is expressed in the brain at E14 and E15 in neuronal populations located in the choroid plexus and mesencephalon, respectively (Nissinen et al. 1995; Karlstedt et al. 2001a; Wiener et al. 2003). From E14 to E18, efferents from the transient mesencephalic HAergic neurons (see below) are detected in the ventral tegmental area and within the medial forebrain and the optic tract from where they send projections to the frontal and parietal cortices (Auvinen and Panula 1988; Panula et al. 1988; Vanhala et al. 1994). Of notice, the groups of cells that produce HA in the mesencephalon during development are different from those present in the tuberomamillary nucleus after birth. There is also evidence that HA receptors are expressed throughout CNS embryonic development and in situ hybridization studies have shown that the patterns of H1- and H2(a)


Fig. 1 Histamine and neuronal differentiation. Neural stem cells follow an intrinsic sequence for in vivo development. (a) In rat, neurogenesis peaks at E14 (pink), when the initial phase of gliogenesis (green) is taking place. The neurogenic peak coincides with the highest level of histamine in the developing brain. (b) The intrinsic sequence of neural stem cells is conserved in vitro, and treatment of gliogenic P2 cells with histamine partially reverses the sequence to an earlier stage via H1 receptor activation, which leads to an increase in neuron differentiation alongside a decrease in glial phenotype. E, embryo day; P, passage in culture. Elaborated from references (Vanhala et al. 1994; Sauvageot and Stiles 2002; Chang et al. 2004; Molina-Hernandez and Velasco 2008).

receptors (H1Rs and H2Rs) expression differ from that of H3Rs. While the first two receptors are extensively expressed from E14 and E15, respectively, and throughout the developmental CNS, at E15, H3Rs can only be identified in the ventral mescencephalon and spinal cord, with later expression in the cerebral cortex at E19 (Kinnunen et al. 1998; Heron et al. 2001; Karlstedt et al. 2001b, 2003). Neural stem cells (NSCs) express H1Rs, H2Rs, and H3Rs in vitro, and HA increases the proliferation of cortical neuroepithelial cells in the presence of basic fibroblast growth factor via H2R activation, while promoting neuronal differentiation from cortical and mesencephalic NSCs by activating H1Rs (Molina-Hernandez and Velasco 2008). Taken together, these data indicate the presence of an active HAergic system during CNS development, although the precise physiological role of HA is still unclear. Herein, we first summarize the functional properties of the four receptors mediating HA actions, and then review the evidence supporting a role for HA in brain development.

Histamine receptors H1 receptors The human H1R is a 487-amino acid peptide whose coding gene is located on chromosome 3 in 3p25 (gene ID 3269). H1Rs interact with Gaq/11 proteins to activate phospholipase C (PLC) promoting, thus, inositol 1,4,5-trisphosphate (IP3)dependent release of Ca2+ ions from intracellular stores and diacylglycerol-mediated activation of protein kinase C. The release of Ca2+ from intracellular stores leads to the opening of plasma membrane store-operated Ca2+ channels (Brown et al. 2002; Sergeeva et al. 2003b) and the activation of the sodium/calcium exchanger (NCX) (Sergeeva et al. 2003a). Other signaling pathways triggered by H1R activation include the production of arachidonic acid, nitric oxide (NO) (Prast and Philippu 2001), and cGMP (Richelson 1978) through pertussis toxin-sensitive Gai/o protein-mediated stimulation of phospholipase A2 (PLA2), Ca2+-dependent NO synthases, and NO-dependent guanylyl cyclases, respectively. Importantly, H1Rs activate AMP-kinase, a checkpoint in the control of energy metabolism (Kim et al. 2007), and nuclear factor kappa B (NF-jB), a key transcription factor controlling genomic imprints and readout (Bakker et al. 2001) (Fig. 2). Radioligand binding has shown H1Rs to be expressed throughout the adult mammalian brain, with high densities in regions related to neuroendocrine, behavioral, and nutritional state control, such as the hypothalamus, aminergic and cholinergic brainstem nuclei, thalamus, and cerebral cortex (Tran et al. 1978; Palacios et al. 1981; Kanba and Richelson 1984; Bouthenet et al. 1988; Martinez-Mir et al. 1990). H1R activation excites neurons in almost all brain regions, including brainstem, hypothalamus, thalamus, amygdala, septum, hippocampus, olfactory bulb, and cerebral cortex

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Fig. 2 Histamine H1 receptor (H1R) main signaling pathways. H1Rs interact with Gaq/11 proteins, which activate several signaling pathways. Ch, channel; DAG, diacylglycerol; ER, endoplasmic reticulum; IAHP, small conductance, Ca2+-dependent K+ current; IP3, inositol-1, 4,5-trisphosphate; NMDA, N-methyl-D-aspartate; NO, nitric oxide; GC, guanylyl cyclase; cGMP, cyclic guanosine monophosphate; NCX, Na+–Ca2+ exchanger; PKC, protein kinase C; PLA, phospholipase A; PLC, phospholipase C.

(Lin et al. 1996; Barbara et al. 2002; Korotkova et al. 2002). Contrastingly, in hippocampal pyramidal neurons, activation of K+ channels through an increase in the intracellular levels of Ca2+ ions ([Ca2+]i) following H1R stimulation decreases cell excitability and inhibits neuronal firing (Selbach et al. 1997). Ca2+-dependent K+ channel activation is also observed in glial cells (Weiger et al. 1997) and cerebellar Purkinje neurons (Kirischuk et al. 1996). The release of Ca2+ ions from intracellular stores is a critical component during ontogenesis and contributes particularly to the formation and maintenance of dendritic structures (Lohmann and Wong 2005). H1R-knockout (KO) mice present increased locomotor activity during the day and a reduction in exploratory behavior in dark and when exposed to new environments (Dai et al. 2007). H2 receptors The gene encoding the human H2R, a 359-amino acid peptide, is located on chromosome 5 in 5q35.5 (gene ID 3274). Distribution of H2Rs in the adult rodent brain using selective radioligands shows a widespread localization and in some areas colocalization with H1Rs. Particularly dense labeling of H2Rs is found in the basal ganglia, amygdala, hippocampus, and cerebral cortex (higher in layers I-III), where a laminar distribution is observed. H2Rs couple to Gas and thus to adenylyl cyclase activation, leading to the formation of cAMP (Hill et al. 2012). This second messenger stimulates protein kinase A, which in turn activates the transcription factor cAMPresponse element-binding protein, both being key regulators of neuronal physiology and plasticity (Widnell et al. 1996).

Fig. 3 Histamine H2 receptor (H2R) main signaling pathways. H2Rs couple to GaS proteins that activate adenylyl cyclases (ACs). ACs produce 3¢-5¢-cyclic adenosine monophosphate (cAMP) that in turn activates protein kinase A (PKA). PKA phosphorylates and activates the hyperpolarization-activated cationic channel (Ih), the small conductance, Ca2+-dependent K+ current (IAHP), voltage-gated potassium channels (Kv3), and cAMP-response element (CRE)-binding protein (CREB).

The hyperpolarization-activated cation channels responsible for the Ih current are directly activated by cAMP (Pedarzani and Storm 1995), and via PKA-dependent phosphorylation H2R activation reduces a Ca2+-activated K+ conductance (small K) responsible for the accommodation of firing and the long-lasting after-hyperpolarization that follows action potentials in pyramidal cells (Haas and Konnerth 1983; Pedarzani and Storm 1993), and regulates fast spiking by modulating Kv3.2-containing K+ channels in interneurons (Atzori et al. 2000). Another consequence of H2R activation is the inhibition of PLA2 and arachidonic acid release, an effect independent of either cAMP or [Ca2+]i levels (Traiffort et al. 1992) (Fig. 3), and the excitation of pyramidal cells (Yanovsky and Haas 1998) and thalamic neurons (McCormick and Williamson 1991), probably through adenylyl cyclase activation (Pedarzani and Storm 1995). H2Rs have been shown to possess constitutive activity (Bakker et al. 2004), defined as receptor activity in the absence of any ligand. H2R-KO mice exhibit selective cognitive deficits with loss of hippocampal long-term potentiation, LTP (Dai et al. 2007), and abnormalities in nociception (Mobarakeh et al. 2006), gastric secretion, and immune functions (Teuscher et al. 2004). The phenotypes observed in H2R-KO mice show similarity with those present in H1R-KO mice (Ogawa et al. 2009). For instance, HA inhibition of methamphetamine-induced locomotor hyperactivity and stereotyped behaviors is still present in H1R- or H2R-KO mice, but not in double H1/2R-KO mice, suggesting an effect mediated by both H1 and H2 receptors with synergistic actions, presumably at the level of the basal ganglia.

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H3 receptors The gene (Hrh3) encoding the human H3R, a 445-amino acid peptide, is located on chromosome 20 in 20q13.33 (gene ID 11255), contains two or three introns, and yields a large number of splice-derived receptor variants with different distribution and pharmacology (Drutel et al. 2001). Through their coupling to pertussis toxin-sensitive Gai/o proteins, H3Rs inhibit the opening of N- and P/Q-type voltage-activated Ca2+ channels and the activity of adenylyl cyclases (Takeshita et al. 1998; Torrent et al. 2005; MorenoDelgado et al. 2006). H3Rs can also engage Gaq/11-mediated signaling and activate PLA2, Akt/GSK3 (Bongers et al. 2007), and mitogen-activated protein kinase (MAPK) pathways (Giovannini et al. 2003) (Fig. 4), all of which play important roles in axonal and synaptic plasticity. An important property of H3Rs is their high degree of constitutive activity (Arrang et al. 2007). H3Rs are heterogeneously distributed in brain areas known to receive histaminergic projections and high densities are found in anterior parts of the cerebral cortex, hippocampus, amygdala, nucleus accumbens, striatum, olfactory tubercles, cerebellum, substantia nigra, and brainstem (Pollard et al. 1993). As autoreceptors on dendrites and axons of the tuberomamillary nucleus neurons, H3Rs inhibit cell firing and histamine synthesis and release from varicosities (Torrent et al. 2005; Haas et al. 2008). Pre-synaptic heteroreceptors, H3Rs, control the release of a variety of other transmitters, namely noradrenaline (Schlicker et al. 1999), dopamine (Schlicker et al. 1993), serotonin (Schlicker et al. 1988), acetylcholine (Blandina et al. 1996), glutamate (Molina-Hernandez et al. 2001), GABA (Garcia et al. 1997), and neuropeptides (Ohkubo et al. 1995).

H3R-KO mice show behavioral state abnormalities, reduced locomotion, metabolic syndrome with hyperphagia, late-onset obesity, increased insulin and leptin levels, and increased severity of neuroinflammatory diseases (Toyota et al. 2002). H4 receptors The H4R is the most recently discovered member of the subfamily of HA receptors (Zhu et al. 2001). The receptor is predominantly expressed in hematopoietic cells and appears to play a role in inflammation (O’Reilly et al. 2002; Dijkstra et al. 2008) and allergy (Dunford et al. 2006). In the gastrointestinal tract, H4Rs are expressed in paracrine cells where they are involved in the regulation of gastric acid secretion, gastric mucosal defense, intestinal motility and secretion, visceral sensitivity, inflammation, immunity, and carcinogenesis (Coruzzi et al. 2012). H4Rs have also been linked to rheumatoid arthritis (Ikawa et al. 2005) and colon and breast cancer (Masini et al. 2005; Maslinska et al. 2006). There is evidence that H4Rs are expressed by other cell types, and receptor mRNA has been detected in discrete brain regions (Coge et al. 2001; Connelly et al. 2009), although other studies have failed to detect H4Rs in the brain (see for instance Nakamura et al. 2000). By using inmunohistochemistry, patch-clamp electrophysiology, and selective pharmacological probes, Connelly et al. (2009) reported that H4Rs are functionally expressed in the CNS. Recently, Ferreira et al. (2012) showed that H4Rs are expressed in a microglia-derived cell line as well as in primary microglia cell cultures from rat cortex, and that HA acting via H4Rs has dual effects on microglia-induced responses: (i) stimulation of microglia motility that involves the expression of a5b1 integrin and the participation of p38 MAPK and Akt signaling pathways, and (ii) in an inflammatory context, inhibition of microglia migration. A recent study showed that H4R-KO mice develop more severe experimental allergic encephalomyelitis than control animals, with impairment of the anti-inflammatory response because of fewer T regulatory cells in the CNS during the acute phase of the disease alongside an increase in the proportion of Th17 cells (del Rio et al. 2012).

Histamine and CNS development

Fig. 4 Histamine H3 receptor (H3R) main signaling pathways. H3Rs interact with Gai/o proteins whose ai/o subunits inhibit adenylyl cyclases (ACs), consequently reducing the synthesis of cAMP and thus its downstream pathways. The bc complexes released upon activation of Gai/o proteins bind to and inhibit voltage-activated Ca2+ channels. VACCs, voltage-activated Ca2+ channels.

The transient histaminergic system The ontogenesis of the HAergic system has been studied since 1962, focusing on limited periods of fetal development. Several studies analyzed the levels of HA and the activities of its synthesizing (histidine decarboxylase) and metabolizing (histamine methyltransferase) enzymes in rat, guinea pig, and chick in total fetus or embryo brain (Kameswaran and West 1962; Schwartz et al. 1971; Tuomisto 1977), and Mezei and Mezei (1978) measured histamine contents in

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some specific areas of the chick embryo nervous system, namely cerebellum, cerebral hemisphere, thalamus, sciatic nerve, and pineal gland, showing that HA levels in cerebral hemisphera and thalamus were higher before hatching. In 1988, Auvinen and Panula detected for the first time the presence of HAergic neurons in the embryo developmental brain. At E13, these cells are located in the mesencephalon and metencephalon, and at E15 in the ventral mesencephalon and rhombencephalon. These neurons constitute the so-called transient HAergic system, the HA-immunoreactive neurons in these areas are different from those detected in the tuberomamillary nucleus of the adult brain, which appear at E20 when hindbrain neurons are no longer detected. These data show that HA is one of the first neurotransmitters to appear in the developmental brain (Auvinen and Panula 1988; Vanhala et al. 1994; Kinnunen et al. 1998). HAergic nerve fibers can be first seen at E15 in the rhombencephalon and the mesencephalon, and in some areas of the diencephalon including the mamillary bodies and frontal cortex. By E18, HA-immunoreactive nerve fibers in the hindbrain decrease, and appear in the olfactory bulb, septal, and hypothalamic areas and cerebral cortex. Finally, HA-positive fibers in the brain increase until post-natal day 14, when the pattern of neurons and fibers resembles that reported for the adult animal (Auvinen and Panula 1988). Noticeably, a subgroup of serotonergic neurons that belong to the developing raphe nuclei coexpress histamine between E14 and E18, and thus form part of the transient HAergic system. After E18, HA-immunoreactivity gradually disappears in the rhombencephalon and the serotonergic neurons continue to establish their adult position (Wada et al. 1991b). The identification of histidine decarboxylase by hybridization in situ and immunohistochemistry supports that these transient 5-HT/HA neurons indeed synthesize HA during brain development (Vanhala et al. 1994; Kinnunen et al. 1998). Furthermore, the transient system may not be the only HA source in the developmental CNS, because several organs produce HA during development and the blood–brain barrier is not yet functional at this time (Kahlson

et al. 1960), allowing for the diffusion of plasmatic HA into the embryonic cerebral tissues. In addition, mast cells may contribute to HA levels during development, although they are detected on the surface of the developing brain after E17, indicating they do not contribute to HA levels before E18 (Auvinen and Panula 1988; Panula et al. 1988). Expression of histamine receptors in the developing CNS Histamine H1 receptors By using a rat H1R full-length cDNA probe and in situ hybridization, Kinnunen et al. (1998) determined the distribution of the H1R mRNA in the developing rat CNS from E14 to E20, showing that a strong signal is already present at E14 in the spinal cord, the rhombencephalon, and the ventricular neuroepithelium of the forebrain (Table 1). By E18, the uniform signal observed in the spinal cord becomes discrete and concentrates in the dorsal and ventral horns/ dorsal and ventral funiculi. At this stage, positive signals continue in the developing cerebral cortex, the ventricular neuroepithelium and the marginal zone, but the cortical preplate and the intermediate zone clearly remain devoid of H1R expression. At E20, the stratified hybridization signal for the receptor in the cerebral cortex diminishes, but a strong signal is still seen in the developing neuroepithelium and in the subplate (Kinnunen et al. 1998). Remarkably, the positive signal obtained by in situ hybridization is not limited to regions containing HAergic nerve fibers suggesting that in some areas such as cerebral cortex, HA originates from sources other than neurons (Auvinen and Panula 1988; Vanhala et al. 1994). Histamine H2 receptors Little is known about H2R expression during CNS development. At E15, the expression pattern of H2R is very uniform in the rat brain, and is clearly distinguishable in some nuclei. The first nuclei to express this receptor are those of the raphe area in its caudal and rostral parts. By E17, the ventral hypothalamus and the cortical plate present clear hybridiza-

Table 1 Localization and levels of histamine receptors in rat central nervous system development Receptor




Telencephalon Mesencephalon Spinal cord Telencephalon Mesencephalon Spinal cord Telencephalon Mesencephalon Spinal cord

+++ +++ +++







++ +++ +++ ++ ++ nd nd ++ +

++ + nd

+++ ++ ++ ++ ++ nd



+++ +++ nd

++ +++ nd

++ ++

+++ High; ++ low; +, very low; nd, not detected. Elaborated from Kinnunen et al. 1998; Karlstedt et al. 2001b, 2003.

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tion signals for this receptor (Karlstedt et al. 2001b) (Table 1). The presence of H2Rs in E14 and E12 NSCs from the cerebral cortex and the mescencephalic neuroepithelium, respectively, suggests that these receptors are expressed earlier than E15 (Molina-Hernandez and Velasco 2008). Histamine H3 receptors In contrast to H1Rs and H2Rs, H3R expression during rat development is clearly restricted to some areas of the CNS. At E15, the most prominent expression is seen in the midbrain ventricular epithelia, medulla, and spinal cord. At E16, medulla and spinal cord in situ hybridization signals are no longer present and H3Rs begin to be expressed at high levels in the midbrain roof, the hypothalamus, and the nucleus accumbens. Later during development (E19), H3R expression is detected in the cortical plate and deep cortical layers, remaining until the end of intrauterine development (Table 1). Noteworthy, H3R expression coincides with the maturation of HAergic fibers, a pattern not observed for H1 or H2 receptors (Karlstedt et al. 2003). No functional effects of H3R activation have been reported for in vivo CNS development, although NSCs from cortex and midbrain (Molina-Hernandez and Velasco 2008) express the receptor (see below). Histamine H4 receptors As mentioned above, H4R function in the adult CNS is still controversial and there are no reports for this receptor in regard to brain development. Histamine effects on neural stem cells NSCs have proved to be very useful for the study of the intrinsic and extrinsic processes that affect cell proliferation, migration, death, and differentiation related to CNS development, and several studies have shown that histamine exerts a number of receptor-mediated actions on NSCs. Molecular (RT-PCR) and Western blot analysis show cultured NSCs from the prosencephalon and the mesencephalon to express H1Rs, and these receptors appear functional because the exposure to HA increases [Ca2+]i, an effect fully blocked by the H1R-selective antagonist chlorpheniramine (Tran et al. 2004; Agasse et al. 2008). Studies using fetal and adult stem cells indicate that via H1R stimulation, HA is able to increase neuron differentiation (Molina-Hernandez and Velasco 2008; Bernardino et al. 2012). Although similar HA-induced increases in neural differentiation, because of augmented neuron commitment, are reported for both adult subventricular and cerebral cortex neuroepithelium NSCs, differences in cell proliferation, glial differentiation, and apoptotic death are reported. For instance, HA increases fetal NSCs proliferation (manly by H2R activation) during cell proliferation, augments apoptotic cell death, and decreases glial differentiation, but these

actions are not seen in adult SVZ NSCs (Molina-Hernandez and Velasco 2008; Bernardino et al. 2012; Rodrı´guezMartı´nez et al. 2012). HA may promote the proliferation of NSCs and cancer stem cells (Po´s et al. 2005; Molina-Hernandez and Velasco 2008). In contrast, Medina et al. (2009) showed that HA impairs the proliferation of human malignant melanoma cells, probably by increasing hydrogen peroxide levels. These opposite effects may rely on the intrinsic characteristics of the cells under study or the extracellular signals present alongside HA. E14 NSCs from the cerebral cortex neuroepithelium express H2Rs, and HA increases cell proliferation via H2R activation in cultured cerebral cortex NSCs from E14 rats (Molina-Hernandez and Velasco 2008). A reduction in cell proliferation by H2R antagonists has been reported for other cell types such as glia-derived cell lines (Finn et al. 1996). The stem-cell population during development is the result of a number of factors such as the proliferative rate, the ratio between asymmetric and symmetric cell division, and apoptotic cell death (Kilpatrick and Bartlett 1993; Caviness and Takahashi 1995; Takahashi et al. 1995). The effect of HA on the proliferation of undifferentiated cells observed in vitro may thus be important to increase the neural stemcell pool in an early stage of development and at later stages, it could participate in the equilibrium between proliferation and death, because HA increases apoptotic death during cell differentiation (Molina-Hernandez and Velasco 2008). In vivo and in vitro studies are thus required to establish whether H2R activation changes the cell division pattern during the periods of elevated proliferation rate observed in early development and how HA increases apoptotic cell death during neurogenesis, as well as the mechanisms involved in these two antagonistic processes at different time points in the developmental brain. Regarding the reduction in glial phenotype of cultured fetal NSCs induce by HA (Molina-Hernandez and Velasco 2008), in accordance with data by Bernardino et al. (2012) for adult subventricular NSCs, this effect may not be because of HA treatment, because in fetal NSCs H1-, H2-, and H3Rantagonists did not prevent the HA action and 4-day exposure to HA did not affect the expression of gliogenic factors such as Notch1 and Hes5 in proliferating NSCs (Molina-Hernandez and Velasco 2008; Rodrı´guez-Martı´nez et al. 2012). Another important difference between adult and fetal NSCs is that although in both cell types HA increases asymmetric division, the former differentiate to GABAergic neurons by increasing Mash1, Dlx2, and Ngn1 mRNA, whereas fetal NSCs differentiate mainly into glutamatergic FOXP2-positive neurons, by increasing Ngn1 and Prox1 mRNA indicating differential HA actions on adult and fetal neuron differentiation. Interestingly, in adult NSCs, HA increases the number and length of ramifications and growth

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cone-like projections, suggesting that histamine favors axogenesis by activating the JNK and MAPK pathways in growing axons (Bernardino et al. 2012). Particularly, in cultured neuroepithelial stem cells, which give rise to all types of cerebral cortex neurons, HA increases the deep-layer and subplate neuron populations as evaluated by the detection of FOXP2- and calretinin-positive cells, respectively (Molina-Herna´ndez and Velasco 2009; Rodrı´guez-Martı´nez et al. 2012). FOXP2 is a fork-head domain transcription factor whose expression during mammalian CNS development has been described in humans and mouse (Lai et al. 2003). Importantly, the emergence of FOXP2-positive neurons during development matches the HA first peak observed in rats, suggesting that this amine plays an important role in the formation of deep cortical layers (Gaspard et al. 2008). The expression pattern indicates that FOXP2 may influence the development of neural circuits involved in sensory processing, sensory–motor integration, and the control of skilled coordinated movements (Scharff and Haesler 2005; Fisher and Marcus 2006). FOXP2-KO mice have a reduction in the number of ‘‘isolation calls’’ emitted by pups when removed from their mother (Shu et al. 2005), and mutations in the human gene encoding FOXP2 result in cortico-striatal abnormalities and speech and language deficits, implicating this gene in the ontogenesis of the neuronal circuitry involved in those functions (Lai et al. 2001; Takahashi et al. 2003). Calretinin is a 29 kDa calcium-binding protein member of the family of EF-hand proteins, characterized by a variable number of helix-loop-helix motifs with high affinity for Ca2+ ions. This protein is abundantly expressed in interneurons and has neuroprotective capacity by buffering intracellular Ca2+ ions (Druga 2009). The distribution pattern of calretinin during CNS development has been evaluated in the somatosensory cortex of the rat (Weisenhorn et al. 1994; Fonseca et al. 1995; Vogt Weisenhorn et al. 1996), the visual cortex of the monkey (Yan et al. 1995), and in neurons throughout the entire depth of the developing cortex (Schierle et al. 1997) showing that the protein is expressed very early in cortical development (rat E11) with a transient increase in early post-natal development. It has been reported that during embryogenesis, calretinin is involved in processes such as neurite elongation, synaptogenesis, and neuronal migration (Schierle et al. 1997). As mentioned above, HA increases the number and length of ramifications and growth cone-like projections in adult NSCs and increases calretinin-positives cells in fetal NSCs in vitro, suggesting an important role of HA in these processes during fetal brain development (Bernardino et al. 2012). H2Rs are present in E14 NSCs from the cerebral cortex neuroepithelium and HA increases cell proliferation via H2R activation in cultured cerebral cortex progenitors from E14 rats (Molina-Hernandez and Velasco 2008), and a reduction

in cell proliferation by H2R antagonists has been reported for other cell types such as glia-derived cell lines (Finn et al. 1996). Finally, in NSCs, HA induces the emergence of a small population of Cux1-positive cells, not observed under control conditions (Molina-Herna´ndez and Velasco 2009). The Cux proteins (also known as Cut or CDP) are a family of homeobox transcription factors implicated in the regulation of cell proliferation and differentiation (Sansregret and Nepveu 2008), and CUX1 has been identified as a restricted molecular marker for the upper layer (II-III) pyramidal neurons. However, its function in cortical development is largely unknown, although it has been suggested that Cux1 regulates the dendrite morphology of cortical pyramidal neurons (Cubelos et al. 2010; Li et al. 2010). It has also been proposed that Cux1 together with Cux2 are involved in mental retardation (Cubelos et al. 2010), possibly related to inadequate cortical layer formation and/or dendritic growth during development.

Perspectives The evidence available points to a possible role for HA in the adequate formation of cerebral cortex and/or the mesencephalon by regulating processes such as neurite elongation, synaptogenesis, neuronal differentiation, and migration. Several questions emerge regarding the role of HA during CNS development, and it is not clear if this biogenic amine is involved in a global manner in neurogenesis required for the adequate formation of CNS circuits, or exerts selective effects on some nuclei. Because HA is able to activate several metabolic intracellular pathways, the study of the mechanisms by which HA affects cell proliferation, differentiation, and death, as well as neuritic growth will bring about important information on this issues. To elucidate in detail these aspects will require manipulation of the HAergic system at precise stages of in vivo CNS development. Furthermore, it will be important to study the relationship of HA with other factors involved in the formation of the CNS such as the expression and levels of cytokines (epidermal and fibroblastic growth factors, epidermal growth factor, and fibroblast growth factor) and their receptors, both known to be essential for the adequate formation of this system. In particular, there are some critical issues that need being addressed by in vivo and in vitro studies at specific stages of development: (i) Whether H1R activation stimulates neural differentiation, cell migration, and/or neurite growth in fetal NSCs and in vivo embryo development. (ii) Whether H2R activation modifies the cell division pattern during the elevated cell proliferation rates observed throughout early development in vivo.

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(iii) The mechanisms involved in HA-induced increase in apoptotic cell death during neurogenesis. (iv) The mechanisms by which HA participates in these antagonistic processes (cell proliferation/differentiation and apoptosis) at different stages in specific regions of the developing brain. (v) The relationship between HA and cytokines and transcription factors that participate in cell proliferation and death, as well as neural differentiation required for adequate CNS formation, such as members of the transforming growth factor-b family in vitro and in vivo and neurogenic transcription factors like neurogenin, Mash, or NeuroD in vivo. (vi) Whether H4Rs are expressed in fetal NSCs.

Acknowledgements Research of A.M.-H is supported by Instituto Nacional de Perinatologı´a Isidro Espinosa de los Reyes (Me´xico). Research of F.D. is supported by Instituto Nacional de Perinatologı´a Isidro Espinosa de los Reyes and Conacyt (Me´xico). Research of J.-A.A.M. is supported by Cinvestav and Conacyt (Me´xico). All authors declare no conflicts of interest.

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 2012 The Authors Journal of Neurochemistry  2012 International Society for Neurochemistry, J. Neurochem. (2012) 122, 872–882

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