Elsevier

Neuroscience

Volume 114, Issue 1, 18 September 2002, Pages 173-193
Neuroscience

A detailed mapping of the histamine H3 receptor and its gene transcripts in rat brain

https://doi.org/10.1016/S0306-4522(02)00135-5Get rights and content

Abstract

The detailed distribution of histamine H3 receptor mRNAs in rat brain was analyzed by in situ hybridization using a 33P-labelled riboprobe and was combined for the first time with the detailed autoradiographic distribution of the receptor determined in the same animals with [125I]iodoproxyfan, a selective radioligand. The signals generated on adjacent brain sections by each probe were quantified and/or rated and were compared in order to identify neuronal populations expressing the receptor. In addition, the cellular localization of the transcripts within various brain structures was analyzed in sections dipped in a photographic emulsion.

In the cerebral cortex, the strong mRNA expression in intermediate and deep layers indicates the presence of H3 receptors on several types of neurons. The binding is dense except in layer V, suggesting that H3 receptors are located on granule cells and apical dendrites of pyramidal cells. In addition to their localization on monoaminergic afferents, the dense binding in layer IV and strong mRNA expression in thalamic nuclei suggest the presence of heteroreceptors on thalamocortical projections. In the hippocampus, the strong mRNA expression but low binding in pyramidal layers of the CA1 and ventral CA3 fields suggest that H3 receptors are abundant on efferent projections of pyramidal cells. In the dentate gyrus, some binding sites in the molecular layer may correspond to H3 receptors synthesized in granule cells and coexpressed with H1 and H2 receptors in their dendrites. In the basal ganglia, H3 receptors are highly expressed in the striatal complex and olfactory tubercles but not in islands of Calleja. Some of the striatal binding sites may correspond to presynaptic receptors present on afferents. The mRNAs in cortical layer V may encode for heteroreceptors on corticostriatal neurons. The presence of mRNAs in the substantia nigra pars compacta suggests that H3 receptors are located upon nigrostriatal afferents. However, the absence of any signal in the ventral tegmental area indicates that some but not all dopaminergic neurons express H3 receptors. In addition, the homogeneous mRNA expression within the caudate putamen and nucleus accumbens suggests that many striatal H3 receptors are present on medium-sized, spiny projection neurons of both the direct and indirect movement pathways. In agreement, a dense binding, but low mRNA expression, is observed in external and internal pallidum and in substantia nigra pars reticulata. In the amygdala, the dense binding and mRNA expression indicate the presence of receptors on both afferents and projections. In the thalamus, the binding in some association nuclei may correspond to receptors present on neurons emanating from the deep cortical layers that strongly express the mRNAs, as well as receptors on the visual systems. However, the low binding and high mRNA expression in most nuclei indicate that many receptors are present upon thalamic projections. In the hypothalamus, the mRNA expression parallels the density of binding sites and is the highest in the tuberomammillary nucleus. Further investigation is needed to know if the dense binding and mRNA expression observed in other nuclei such as the paraventricular, ventromedial and medial tuberal nuclei correspond to pre- and/or postsynaptic receptors. mRNAs are also observed in several areas projecting to the tuberomammillary nucleus, such as the ventrolateral preoptic nucleus. In the lower brainstem, the high mRNA expression and very low binding in the locus coeruleus and raphe nuclei indicate that presynaptic rather than somatodendritic receptors regulate noradrenaline and serotonin release, respectively. A similar pattern in vestibular nuclei suggests that receptors located on projections account for the anti-vertigo properties of H3 receptor antagonists. In the cerebellum, binding is hardly detectable but a strong mRNA expression is found in most, if not all, Purkinje cells as well as in several central cerebellar nuclei, suggesting the presence of H3 receptors on efferent projections.

The present study reports the first detailed quantification and/or rating of H3 receptor mRNAs in the brain. The comparison, performed in the same animals, with the distribution of the H3 receptor protein provides evidence for the presence of H3 receptors on many neuronal perikarya, dendrites and projections. Although some localizations, mainly as auto- or heteroreceptors, are consistent with previous functional studies, the physiological role, if any, of most of these presynaptic or postsynaptic receptors remains to be established.

Section snippets

Tissue preparation

All experiments performed in the present study conformed to the National Institutes of Health guidelines (décret no. 2001-464, May 29, 2001, from the French Ministry of Agriculture). Male Wistar rats (Iffa-Credo, L’Arbresle, France) were killed by decapitation, their brain was removed rapidly, immediately frozen (−40°C) by immersion in monochlorodifluoromethane and stored at −70°C. Brain sections (10 μm) were prepared on a cryostat and thaw-mounted onto Superfrost slides. For in situ

Results

The densities of [125I]iodoproxyfan binding sites and H3R mRNAs in the various structures were quantified and/or arbitrarily rated and the results are given in Fig. 1 and Table 1, Table 2, Table 3, Table 4, Table 5.

Autoradiograms from sagittal or frontal sections generated with [125I]iodoproxyfan or with a selective antisense riboprobe are shown in Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6. Fig. 7, Fig. 8, Fig. 9 display the cellular localization of H3R mRNAs in sections from various brain areas.

Discussion

The aim of the present work was to rate and compare the detailed autoradiographic distributions of the H3R and its gene transcripts on adjacent brain sections from the same rats, using two selective probes, i.e. the radioligand [125I]iodoproxyfan (Ligneau et al., 1994) and a 33P-labelled riboprobe corresponding to a partial coding sequence (∼600 bp) of the rat H3R and detecting all the previously cloned functional isoforms of the receptor (Morisset et al., 2001, Héron et al., 2001). The

Conclusion

The present study provides evidence for the expression of H3Rs upon many neuronal cell types. If some localizations are consistent with previous functional studies, the physiological role of many of the receptors present on neuronal perikarya, dendrites and/or projections remains to be understood. Moreover, many of these localizations do not parallel the histaminergic innervation, and the question then arises as to how these receptors are activated. We showed recently that native H3Rs in rodent

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