Histamine H1 and H3 receptors in the rat thalamus and their modulation after systemic kainic acid administration

Experimental Neurology 194 (2005) 43 Y 56 www.elsevier.com/locate/yexnr

Histamine H1 and H3 receptors in the rat thalamus and their modulation after systemic kainic acid administration CongYu Jina, Minnamaija Lintunena, Pertti Panulaa,b,T a

Department of Biology, A˚ bo Akademi University, BioCity, Tykistokatu 6A, FIN-20520 Turku, Finland b Neuroscience Center, Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland Received 22 October 2004; revised 7 January 2005; accepted 19 January 2005 Available online 12 March 2005

Abstract In rat thalamus, histamine H1 receptor and isoforms of H3 receptor were expressed predominantly in the midline and intralaminar areas. Correspondingly, higher H1 and H3 receptor binding was also detected in these areas. All isoforms of H3 receptor were expressed in several thalamic nuclei, but there were minor differences between their expression patterns. H1 mRNA expression was high in the ventral thalamus, but the H1 binding level was low in these areas. Since increased brain histamine appears to have an antiepileptic effect through the H1 receptor activity, kainic acid (KA)-induced status epilepticus in rat was used to study modulation of H1 and H3 receptors in the thalamus following seizures. After systemic KA administration, transient decreases in mRNA expression of H1 receptor and H3 receptor isoforms with full-length third intracellular loops were seen in the midline areas and the H1 receptor mRNA expression also decreased in the ventral thalamus. After 1 week, a robust increase in mRNA expression of H3 receptor isoforms with a full-length third intracellular loop was found in the ventral posterior, posterior, and geniculate nuclei. The changes indicate a modulatory role of H3 receptor in the sensory and motor relays, and might be involved in possible neuroprotective and compensatory mechanisms after KA administration. However, short-term increases in the H3 receptor binding appeared earlier (72 h) than the increases of H3 mRNA expression (1Y4 w). The elevations in H3 binding were evident in the intralaminar area, laterodorsal, lateral posterior, posterior and geniculate nuclei, and were likely to be related to the cortical and subcortical inputs to thalamus. D 2005 Elsevier Inc. All rights reserved. Keywords: Status epilepticus; mRNA expression; Receptor binding; H3 receptor isoforms

Introduction

Abbreviations: AD, anterodorsal nucleus; AM, anteromedial nucleus; AV, anteroventral nucleus; CM, central medial nucleus; DLG, dorsal lateral geniculate nucleus; Hb, habenular nucleus; iml, internal medullary lamina; LD, laterodorsal nucleus; LP, lateral posterior nucleus; MD, mediodorsal nucleus; MG, medial geniculate nucleus; PF, parafascicular nucleus; Po, posterior nuclear group; PV, paraventricular nucleus; Re, reuniens nucleus; Rh, rhomboid nucleus; Rt, reticular nucleus; SPFPC, subparafascicular nucleus, parvicellular part; VA, ventral anterior nucleus; VL, ventrolateral nucleus; VM, ventromedial nucleus; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus; VPPC, ventral posterior nucleus, parvicellular part; VLG, ventral lateral geniculate nucleus; ZI, zona incerta. T Corresponding author. Neuroscience Center, Institute of Biomedicine/ Anatomy, University of Helsinki, POB 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. Fax: +358 9 191 25261. E-mail address: [email protected] (P. Panula). 0014-4886/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2005.01.012

Various pathological states, including brain damage, cortical dysgenesis, vascular malformations, mutations, or dysfunctions of ion channels, induce seizures. Many brain structures take part in the genesis of the characteristic rhythmic firing during seizures. Among them, the limbic system and the neocortex have drawn most attention. The thalamus has extensive connections to the neocortex and other subcortical structures, and its role in seizures has been emphasized (Avanzini et al., 2000; Bertram et al., 1998; Cassidy and Gale, 1998; Debay et al., 2001; Hamani and Mello, 2002). The thalamus serves as the gateway to the cortex since it conveys both external and internal messages to the cortex. Moreover, the thalamus serves as a central switchboard that is essential for the brain oscillations

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(Steriade et al., 1997). As a component of major basal ganglia loops (reviewed by Nakano, 2000), the thalamus, especially the midline thalamic areas, the mediodorsal nucleus (MD), and the intralaminar areas, are crucial for maintaining the normal limbic functions (Bertram et al., 2001; Cassidy and Gale, 1998; Juha´sz et al., 1999; Patel et al., 1988; Zhang and Bertram, 2002). Many neurotransmitters, such as glutamate, GABA, dopamine, acetylcholine, and histamine, have been found to underlie the mechanisms of seizures (Baptista et al., 1994; Deransart et al., 2001; Gruslin et al., 1999; Meldrum et al., 1999; Olsen et al., 1999; Scherkl et al., 1991; Weinshenker and Szot, 2002). However, most antiepileptic drugs either enhance the GABAergic function or inhibit the action of voltage-gated sodium channels directly. The role of histamine (and H1 receptor ligands) through H1 receptors may be independent of GABA and affect neuronal excitability (Haas and Panula, 2003). It has been reported that in histidinemic patients, whose brain histamine content is higher compared to normal individuals, the incidence of convulsions during childhood is much lower than that of normal children (Yokoyama, 2001). Thioperamide and clobenpropit, antagonists and inverse agonists of the H3 receptor, an autoreceptor that inhibits the synthesis and release of histamine (Arrang et al., 1983), decrease the duration of electrically induced convulsions in mice (Yokoyama et al., 1993a, 1994), and inhibit amygdaloid kindled seizures (Kakinoki et al., 1998). The combination of subeffective doses of thioperamide and the antiepileptic drugs phenytoin and gabapentin also protects against electrically or pentylenetetrazole (PTZ)induced seizures in mice (Vohora et al., 2001). In addition, other H3 receptor antagonists, iodophenpropit and AQ-0145, also show antiseizure effects (Harada et al., 2004; Murakami et al., 1995). The anticonvulsive effects of the H3 receptor antagonists may be due to an increase in endogenous brain histamine release (Arrang et al., 1983). Several lines of evidence thus support a protective role of histamine in seizures. However, activation of the H3 receptor affects the release of many other potentially important neurotransmitters as well (Haas and Panula, 2003). Both clinical and experimental evidence suggests that H1 receptor antagonists induce seizures in patients and kindling, a chronic experimental model of human complex partial seizures, in rats (Churchill and Gammon, 1949; Schwartz and Patterson, 1978; Wyngaarden and Seevers, 1951; Yokoyama et al., 1993b, 1996). H1 receptor antagonists can prolong the duration of electrically induced convulsions in developing mice (Yokoyama, 2001). Moreover, increased H1 receptor density is found in the temporal cortex of patients with complex partial seizures (Iinuma et al., 1993). All these findings suggest that brain histamine has an anticonvulsive effect through H1 receptor action. The assumption has been confirmed by the study on both H1 receptor and histidine decarboxylase (the only enzyme that catalyzes the synthesis of brain histamine) gene knockout mice (Chen et al., 2003). In animals that either have very

low brain histamine content (histidine decarboxylase-deficient mice) or lack the H1 receptor, the development of the PTZ-induced seizures is accelerated, confirming the suppressive role of histamine through H1 receptor in the seizure generation. So far, most investigations on the anticonvulsive role of histamine have focused on electrically- or PTZ-induced seizures. The possible role of histamine in temporal lobe epilepsy and the brain regions affected are still unclear. In this study, we examined the modulation of histamine receptors in the thalamus of rats treated systemically with kainic acid (KA). KA is an analogue of the major excitatory neurotransmitter glutamate (Olney and Rhee, 1974), which causes excitotoxicity in the limbic areas via the activation of the AMPA and kainate subtypes of the ionotropic glutamatergic receptors and induces status epilepticus. Systemic administration of KA in rats has been used as an animal model of human temporal lobe epilepsy. Since the brain damage and subsequent spontaneous seizures last long, the model is useful for studying both the development of temporal lobe epilepsy and compensatory mechanisms (reviewed by Ben-Ari, 1985; Ben-Ari and Cossart, 2000; Sperk, 1994). At least six functional H3 receptor isoforms (H3AYF) have been identified in rat (Drutel et al., 2001; Hough and Leurs, 2002). The differences between the H3A, H3B, and H3C isoforms are located in the middle of the third intracellular loop (IC3). The H3A isoform is the full-length one, whereas H3B and H3C isoforms result from deletions of 32- and 48amino-acid domains in IC3, respectively. Moreover, substitution of the seventh transmembrane (TM7) domain and C-terminus in addition to the changes in IC3 yield three additional isoforms: H3D, H3E, and H3F. These three isoforms have the same alternative TM7 domain and Cterminus as a result of splicing of the putative fourth intron, but their IC3 loops are different. The IC3 loop of H3D is the same as that of H3A, whereas the IC3 loops of H3E and H3F are identical with those of H3B and H3C, respectively. The H3DYF isoforms are not able to bind ligands but may regulate the expression of other isoforms (Bakker et al., 2003). The mRNA expression of H1 and H3 receptor isoforms was studied in normal and KA-treated rat thalamus, a crucial brain structure involved in limbic seizures and KA-mediated damage. Correspondingly, H1 and H3 receptor binding was studied in the same materials. Although H3A, H3B, and H3C isoforms are all coupled to the Gi/o-mediated responses (Clark and Hill, 1996; Garbarg et al., 1989) and inhibit the cAMP formation (Lovenberg et al., 1999), differences in their signaling pathways were found (Drutel et al., 2001). It has been demonstrated recently that the H3A isoform potently activates p42/44 MAPK pathway (Drutel et al., 2001), which may in turn activate CREB, an important protein in neuronal survival (Tanaka, 2001; Walton and Dragunow, 2000). Thus, the investigation on H3 receptor mRNA expression after KA treatment was focused on the H3A and H3D isoforms that were detected by the same probe.

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Materials and methods Animal data Three 2-month-old male SpragueYDawley rats injected with 0.9% NaCl were used as controls. For the KA administration experiment, KA (15 mg/kg) was injected subcutaneously to 2-month-old male SpragueYDawley rats at the concentration of 10 Ag/Al. The same volume of 0.9% NaCl was injected to the control animals. After injection, rats were kept for 3 h, 6 h, 12 h, 24 h, 72 h, 1 w, and 4 w, then killed. The brains were quickly removed, frozen in the precooled isopentane and kept at j70-C until sectioning. For each time point, three animals were used. Permits for the experiments were obtained from the Committee for Animal Experiments of the Abo Akademi University, and from the Office of the Regional Government of Western Finland. Tissue preparation Rat brains were equilibrated and sectioned at 20 Am on a cryostat at j20-C, thaw-mounted on poly-l-lysine-coated slides, and rapidly frozen again. The slides were stored at j70-C until used. In situ hybridization Probes A 45-mer-oligonucleotide was generated according to the published rat H1 receptor sequence (Fujimoto et al., 1993). The probe (GGG ACG TGT TTC CCT TTC CCC CTC TTG GCT GAA GAC AGT TGG AGA) was complementary to nucleotides 850Y894 in IC3 of the rat H1 receptor cDNA and it has been used for detecting rat H1 receptor mRNA expression (Lintunen et al., 1998). The mRNA expression of H3 receptor isoforms was revealed with three synthetic oligonucleotide probes (Drutel et al., 2001). Probe A, a 46-mer-oligonucleotide (CGA GGG CAG CCT CCC CAG CCT CAA CAC CAG GGC CTG CCT CAC CCA C) that was complementary to nucleotides 829Y874 in IC3 of the rat H3 receptor cDNA, detected the H3A and H3D isoforms that both have fulllength IC3. Probe B, a 50-mer-oligonucleotide (AGT GCC CCT TGA GGA GCT GCC AGA GCT GTG CAA CGG CAT GGC CTC GCC AT) that was complementary to nucleotides 797Y821 and 918Y942, was designed to detect the H3B and H3E isoforms that both have a deletion between nucleotides 821 and 918 in IC3. Probe C, a 50-meroligonucleotide (CTG AAG ATG CTG ATG GCT TGG AGC CCC TGT GCA ACG GCA TGG CCT CGC CA) that was complementary to nucleotides 798Y821 and 966Y991, was used to detect the H3C and H3F isoforms that both have a deletion between nucleotides 821 and 966 in IC3. The oligonucleotide probes were 3V-end labeled with 5V-a(thio)triphosphate-[35S] (NENi Life Science Products, Inc., Boston, MA, USA) using terminal deoxytransferase (Prom-

45

ega, Madison, WI, USA). Addition of 100-fold excess unlabeled probe was performed as a control in each hybridization experiment. An unrelated probe of identical length labeled to the same specific radioactivity was used as another control. Hybridization procedure Hybridization was carried out as described by Lintunen et al. (1998). The sections were hybridized overnight at 42-C for detecting H1 receptor or 50-C for detecting H3 receptor isoforms in a reaction mixture of probes and hybridization solution, then went through a washing step at 56-C. After dehydration, the sections were exposed to Kodak BioMax MR-film (Scientific Imaging System, Eastman Kodak Company, Rochester, NJ, USA) together with 14 C-standards (American Radiolabeled Chemicals, St. Louis, MO, USA) for either 10 d (H1 receptor) or 20 d (H3 receptor isoforms). Film images were analyzed by a computer-based MCID image analysis system (Imaging Research, St. Catherines, Ontario, Canada). Receptor binding autoradiography H1 receptor radioligand binding The procedure for H1 receptor radioligand binding was the same as described previously (Lintunen et al., 2001a). Sections were incubated at room temperature for 45 min in 50 mM Na/K phosphate buffer (pH 7.4) containing 5 nM [3H]-mepyramine (NENi Life Science Products, Boston, MA, USA). Adjacent sections were incubated in the presence of additional 2 AM triprolidine (kindly provided by Professors H. Timmerman and R. Leurs, LeidenAmsterdam Center for Drug Research, the Netherlands) and used as controls. After washing with the same phosphate buffer 4  2 min at 0-C, the sections were rinsed with the ice-cold water and dried under a stream of cold air. The sections were then exposed to Hyperfilm (Amersham International, Buckinghamshire, UK) together with 3H-standards (Amersham International, Buckinghamshire, UK) for 8 w. The film images were analyzed by the computer-based MCID image analysis system. H3 receptor radioligand binding The procedure for H3 receptor radioligand binding was based on the description of Ryu et al. (1996) with minor modifications and was described in our earlier publication (Lintunen et al., 2001b). Sections were incubated for 45 min at room temperature in 150 mM Na/K phosphate buffer (pH 7.4) containing 100 AM dithiothreitol (DTT), 2 mM MgCl2, and 4 nM [3H]-Na-Methylhistamine ([3H]-NAMH; NENi Life Science Products, Boston, MA, USA). Adjacent sections were incubated in the presence of additional 5 AM clobenpropit (kindly provided by Professors H. Timmerman and R. Leurs) and used as controls. After incubation, sections were washed 4  30 s with the same buffer at 0-C, rinsed with ice-cold water, and dried under a stream of cold air. The sections were then exposed to Hyperfilm together with 3H-

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standards for 5 w. The film images were analyzed by the computer-based MCID image analysis system. Quantification and statistical analysis Quantification was carried out as described earlier (Jin et al., 2002). The film images were digitized and the optical densities were converted to the linear gray scale values by using a 14C- or 3H-standard derived curve. The nuclear boundaries were identified from cresyl violet-stained sections from the same series of sections based on the atlas of rat brain (Paxinos and Watson, 1997). The distribution patterns of mRNA expression and receptor binding in the normal rat thalamus were based on the measurements obtained from

three rats. Five to 20 measurements on different levels were made from each nucleus of every animal. Bar graphs showing mRNA expression or receptor binding levels in all thalamic nuclei were produced from each brain. The variation between individuals was minor, and the quantitative values presented in Table 1 cover the whole range of observed values. In each brain, the highest expression or binding level in the thalamus was set to 100%, while the average value obtained from the control hybridizations was set to 0. The +/j to +++ values in Table 1 were classified as follows: very low +/j is 0Y15%, low + is 15Y40%, moderate ++ is 40Y70%, high +++ is 70Y100% of maximum signal intensity in the thalamus. For the H3 receptor mRNA expression detected by probes A and B, the expression

Table 1 Regional distribution in the normal rat thalamus of histamine receptor mRNA expression (H1 receptor, and H3 receptor isoforms) and H1 and H3 receptor binding Abbreviations

H1 mRNA

H1 binding

H3 mRNA detected by probe A

H3 mRNA detected by probe B

H3 mRNA detected by probe C

H3 binding

Anterior nuclear group Anterodorsal nucleus Anteroventral nucleus Anteromedial nucleus

AD AV AM

++/+++ +/++ +

+/++ + +

+/++ +/++ +

+/j +/j +/j

+ + +

+ + +/++

Mediodorsal nucleus

MD

+

+/++

+/++

++

+/++

+/++

Midline area and intralaminar nuclei Paraventricular nuclei Central medial nucleus Internal medullary lamina Parafascicular nucleus Rhomboid nucleus Reuniens nucleus

PV CM iml PF Rh Re

++/+++ ++/+++ ++ ++ ++ ++

++/+++ ++ +/++ +/++ ++/+++ ++/+++

++ ++ +/++ + ++ +/++

++ ++ ++ ++ +/++ +

+++ ++ +/++ + ++/+++ ++

+++ ++/+++ ++ + ++/+++ +++

Lateral dorsal area Laterodorsal nucleus Lateral posterior nucleus

LD LP

+/++ +/++

+/++ +

+/++ +

+/++ +/++

+ +

++ ++

Ventral nuclear group Ventral anterior nucleus Ventrolateral nucleus Ventral posterolateral nucleus Ventromedial nucleus Ventral posteriomedial nucleus Ventral posterior nucleus, parvicellular part Subparafascicular nucleus, parvicellular part

VA VL VPL VM VPM VPPC SPFPC

+ +/j +/j + +/j +/j +/j

+ + +/j + +/j + +

+ +/++ + + +/++ + +

+/j +/++ + +/++ +/++ +/++ +/j

+ +/++ +/++ + +/++ + +

+ + +/j +/++ +/j + +

Posterior nuclear group

Po

+

+

+

++

+/++

+

Geniculate nuclei Dorsal lateral geniculate nucleus Medial geniculate nucleus

DLG MG

+/++ ++

+/++ +

+ +/++

+/++ +/++

+/++ +/++

+ +/++

Habenular nucleus

Hb

+/++

+/++

+

+/j

+/j

+/j

Ventral thalamus Reticular nucleus Zona incerta Ventral lateral geniculate nucleus

Rt ZI VLG

+++ +++ ++

+ +/++ +/++

+ + +

+ + +/++

+ + +/j

+ + +

Values presented are the averages of three different brains based on the film image measurements using the computer-based MCID image analysis system. +/j, very low; +, low; ++, moderate; +++, high. The nuclear parcellation is based on Paxinos and Watson (1997).

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patterns were fairly even and the intensities were low, therefore, the highest expression level was set as ++. The +/j to ++ values in Table 1 for mRNAs detected by probe A and B were classified as follows: very low +/j is 0Y20%, low + is 20Y60%, moderate ++ is 60Y100% of maximum signal intensity in the thalamus. Three animals were used for each time point after KA injection and measured in the same way. Three batches of in situ hybridization and receptor binding experiments were carried out, and each included one control animal and one KA-treated animal from each time point to allow comparisons. For each batch of experiment, the average value of each thalamic nucleus of the control brain was set as 100%, and the values of each thalamic nucleus measured from the KA-treated brains of the same batch were compared to the average value of the control and converted to relative values. Then, the relative values obtained from three batches of experiments were pooled for statistical analysis. One-way ANOVA (with Bonferroni’s multiple comparison test) was performed to test the significance of differences between KA-treated and control animals in mRNA expression or receptor binding levels in the thalamic nuclei.

Results H1 and H3 receptor mRNA expression and radioligand binding in the rat thalamus The expression patterns of H1 and H3 receptor mRNA and distribution of radioligand binding sites for these receptors are shown in Table 1 and Figs. 1Y3.

47

H1 receptor mRNA expression and radioligand binding in the rat thalamus H1 receptor mRNA expression level was high in the reticular nucleus (Rt) and zona incerta (ZI), moderate to high in the anterodorsal nucleus (AD), the midline areas including the paraventricular nuclei (PV), central medial nucleus (CM), rhomboid nucleus (Rh), and reuniens nucleus (Re), the intralaminar areas including the internal medullary lamina (iml) and parafascicular nucleus (PF), the medial geniculate nucleus (MG) and ventral lateral geniculate nucleus (VLG). The expression level in the habenula (Hb), anteroventral nucleus (AV), lateral dorsal nucleus (LD), lateral posterior nucleus (LP), and the dorsal lateral geniculate nucleus (DLG) was low to moderate. In other thalamic areas, such as MD, the whole ventral nuclear group, and posterior nuclear group (Po), the expression level was low (Figs. 1A, D, G, Table 1). H1 receptor binding level was moderate to high in the midline areas (PV, CM, Rh, Re), low to moderate in AD, MD, iml, PF, LD, DLG, Hb, ZI and VLG, and low in other thalamic nuclei (Figs. 1B, E, H, Table 1). The mRNA expression of H3 receptor isoforms and H3 receptor radioligand binding in the rat thalamus Among the H3 receptor isoforms studied here, mRNA detected by probe A displayed low to moderate expression intensity in the rat thalamus with a fairly even distribution pattern (Figs. 2A, C, Table 1). Moderate expression was found in most of the midline areas (PV, CM, Rh). Low to moderate expression was seen in AD, AV, MD, iml, Re, LD, ventrolateral (VL) and ventral posteromedial (VPM) nuclei, and MG. The expression was low in other thalamic areas.

Fig. 1. Distribution of H1 receptor mRNA (A, D, G) and H1 receptor radioligand binding (B, E, H) in the normal rat thalamus. The scales indicate the intensities of different expression and binding levels. The schematic figures on the right show the most important landmark sites in the thalamus (C, F, I). The distances from bregma (according to the atlas of Paxinos and Watson, 1997) are: AYC, 2.00 mm; DYF, 2.80 mm; GYI, 4.80 mm. Scale bar: 3 mm.

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displayed highest expression intensity among the H3 receptor isoforms in the rat thalamus (Figs. 2I, K, Table 1). The expression level was moderate to high in the midline areas (PV, CM, Rh, Re), low or very low in the anterior nuclear group, PF, LD, LP, Hb, the ventral thalamus (Rt, ZI, VLG), VA, ventromedial nucleus (VM), parvicellular part of ventral posterior nucleus (VPPC), and SPFPC of the ventral nuclear group, and low to moderate in other thalamic areas. H3 receptor binding level was moderate to high in the midline areas (PV, CM, Rh, Re), moderate in iml and lateral dorsal areas (LD, LP), low to moderate in AM, MD, and MG, and low in other thalamic nuclei (Figs. 3A, C, E, Table 1). H1 and H3 receptor mRNA expression and receptor binding after KA administration H1 receptor mRNA expression in the rat thalamus after KA administration At the 12-h time point after KA injection, a significant decrease in the H1 receptor mRNA expression was observed in the midline area (PV, CM, Re), MD, and ventral thalamus (Rt, ZI) as compared to the controls (P G 0.001; Figs. 4AYB, I). 24 h after KA injection, significant decrease in H1 receptor mRNA expression level was still observed in PV, Re (P G 0.001), and MD (P G 0.01), but not in the other nuclei (Fig. 4I). Meanwhile, an increase of expression was seen in MG as compared to the controls (P G

Fig. 2. Distribution of H3 receptor isoform mRNA in the normal rat thalamus. (A, C) mRNA expression detected by probe A. (E, G) mRNA expression detected by probe B. (I, K) mRNA expression detected by probe C. The scales indicate the intensities of different expression levels. The schematic figures on the right show the most important landmark sites in the thalamus (B, D, F, H, J, L). The distances from bregma (according to the atlas of Paxinos and Watson, 1997) are: AYB, 2.20Y2.30 mm; CYD, 4.80Y5.20 mm; EYF, 2.80 mm; GYH, 4.80 mm; IYJ, 3.14 mm; KYL, 4.52Y4.80 mm. Scale bar: 3 mm.

Generally, H3 receptor mRNA detected by probe B displayed the lowest expression intensity and the distribution pattern was quite even (Figs. 2E, G, Table 1). Moderate expression level was seen in MD, PV, CM, iml, PF, and Po. The expression level was very low in Hb, the anterior nuclear group, ventral anterior (VA), and subparafascicular (SPFPC) nuclei. The expression level was low to moderate in the other nuclei. H3 receptor mRNA detected by probe C

Fig. 3. Pattern of H3 receptor radioligand binding in the normal rat thalamus (A, C, E). The scale indicates the intensities of different receptor binding levels. The schematic figures on the right show the most important landmark sites in the thalamus (B, D, F). The distances from bregma (according to the atlas of Paxinos and Watson, 1997) are: AYB, 3.14 mm; CYD, 4.80 mm; EYF, 6.04 mm. Scale bar: 3 mm.

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Fig. 4. The effect of KA on H1 receptor mRNA expression levels. (A, E) H1 receptor mRNA expression in the control thalamus. (B) H1 receptor mRNA expression in the thalamus 12 h after KA administration. PV and MD, CM, Re, Rt, and ZI are indicated by the arrows. (C) H1 receptor mRNA expression 72 h after KA administration. PV is indicated by the arrow. (F) H1 receptor mRNA expression 24 h after KA administration. MG is indicated by the arrow. (G) H1 receptor mRNA expression 72 h after KA administration. (D, H) The schematic figures show the most important landmark sites in the thalamus. The distances from bregma (according to the atlas of Paxinos and Watson, 1997) are: AYD, 3.30 mm; EYH, 5.60Y5.80 mm. (I) Quantification of the relative H1 mRNA expression levels shows changes in areas seen in AYH. The open bars represent the average expression levels in each nucleus of the controls (are set as 100%). The filled bars represent the average relative expression levels in nuclei of the KA-treated animals at different time points. Relative H1 receptor expression levels are shown as mean T SE. The statistical significance obtained from one-way ANOVA (Bonferroni’s multiple comparison test) is indicated by asterisks (*P G 0.05; **P G 0.01; ***P G 0.001). Scale bar: 3 mm.

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0.01; Figs. 4EYF, I). Most of the changes were transient since at the time point of 72 h (Figs. 4C, G, I), no significant differences were detected between the control and experimental thalami except for the reduction of H1 receptor mRNA expression in PV (P G 0.01). No significant changes were detected at later time points. H1 receptor radioligand binding in the rat thalamus after KA administration Few major changes of H1 receptor binding were detected in the rat thalamus after KA injection (Fig. 5). Compared to the controls (Fig. 5A), a transient significant increase of binding in PV (P G 0.05) and a transient significant decrease of binding in Re (P G 0.01) were observed 24 h after KA injection (Figs. 5B, E), but undetected at other

time points (Figs. 5C, E). No other significant changes were found. H3 receptor mRNA expressions detected by probe A in the rat thalamus after KA administration Shortly after KA injection (6 h), significant decreases in H3 receptor mRNA expression detected by probe A were seen in PV (P G 0.05) and Re (P G 0.001) as compared to the controls (Figs. 6AYB, J). The decrease was transient since no statistical significance was obtained between the expression levels in these two nuclei of experimental and control animals at the 72-h and later time points (Fig. 6J). On the contrary, a significant increase in H3 receptor mRNA expression level detected by probe A was seen in Po already 6 h after KA injection (P G 0.01; Fig. 6J), and the increase was also observed at the later time points as long as 4 w after KA injection (P G 0.001; Figs. 6E, J). Moreover, a significant increase in H3 receptor mRNA expression detected by probe A was also seen in VPM, VPL (P G 0.001), DLG, and MG (P G 0.05) 1 w after KA injection and the change was still observed at the 4 w time point (P G 0.001, except in MG, P G 0.01; Figs. 6E, H, J). H3 receptor radioligand binding in the rat thalamus after KA administration A significant decrease in H3 receptor binding level was found in Re (P G 0.05) and MG (P G 0.01) at the 12-h time point after KA injection (Figs. 7B, M) as compared to the controls (Fig. 7A), but not detected at the other time points. At the 72 h time point after the KA injection, increased binding level in iml, LD (P G 0.05), LP, Po, VPM, VPL, DLG, VLG (P G 0.001), and MG (P G 0.05) was found (Figs. 7E, H, K, M) compared to the controls (Figs. 7D, G, J). Although the tendency towards an increase in H3 receptor binding was also seen in MD and CM (Fig. 7E), no statistical significance was obtained (Fig. 7M). Increased binding level in VPM (P G 0.001) and VPL (P G 0.01) was also seen 1 w after KA injection (Fig. 7M). No significant changes in H3 receptor binding levels were found at the other time points.

Discussion

Fig. 5. The effect of KA on H1 receptor radioligand binding levels. (A) H1 receptor binding in the control thalamus. (B) H1 receptor binding in the thalamus 24 h after KA injection. PV and Re are indicated by the arrows. (C) H1 receptor binding in the thalamus 48 h after KA administration. (D) The schematic figure shows some important landmark sites in the thalamus. The distance from bregma (according to the atlas of Paxinos and Watson, 1997) is 3.30 mm. (E) Relative H1 receptor binding levels shown as mean T SE. The open bars represent average relative binding levels of PV and Re in controls and are set as 100%. The filled bars represent average relative H1 binding levels in PV and Re in the KA-treated rats compared to the controls. The statistical significance obtained from one-way ANOVA (Bonferroni’s multiple comparison test) is indicated by asterisks (*P G 0.05; **P G 0.01). Scale bar: 3 mm.

The mRNA expression and receptor radioligand binding of both H1 and H3 receptors exist in the thalamic areas related to seizures The midline thalamus has been considered as a physiological synchronizer of the cortex and multiple independent limbic structures that might be involved in the seizure initiation (Bertram et al., 1998). Both H1 and H3 receptors showed moderate to high mRNA expression levels in most of the midline nuclei. Moderate to high H1 and H3 receptor binding levels were also found in this area. H1 receptor is considered to locate postsynaptically, and thus on the

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Fig. 6. H3 receptor mRNA expression detected by probe A after KA administration. (A, D, G) H3 receptor mRNA expression detected by probe A in the control thalamus. (B) mRNA expression 6 h after KA injection. PV and Re are indicated by the arrows. (E) mRNA expression 1 w after KA administration. Po, VPM, VPL, and DLG are indicated by the arrows. (H) mRNA expression 1 week after KA administration. MG is indicated by the arrow. (C, F, I) The schematic figures show the most important landmark sites in the thalamus. The distances from bregma (according to the atlas of Paxinos and Watson, 1997) are: AYC, 3.14 mm; DYF, 3.80Y4.16 mm; GYI, 4.80Y5.20 mm. (J) Relative H3 receptor mRNA expression levels detected by probe A in different thalamic nuclei based on the quantification are presented as mean T SE. The average expression levels in the controls are set as 100% and presented by the open bars. The average relative expression levels in the KA-treated rats compared to the controls are presented by the filled bars. The statistical significance obtained from one-way ANOVA (Bonferroni’s multiple comparison test) is indicated by asterisks (*P G 0.05; **P G 0.01; ***P G 0.001). Scale bar: 3 mm.

dendritic rather than axonal terminals of the neurons that express H1 receptor mRNA. Our results show that the pattern of H1 receptor mRNA expression correlates well with that of the H1 receptor binding in this area. H3 receptor is an auto- and heteroreceptor that distributes presynaptically in, for example, histaminergic and noradrenergic terminals, and is hence located on the axonal projections of the neurons expressing H3 receptor mRNA. The moderate to high levels of both H3 receptor mRNA expression and H3 receptor binding in the midline thalamic area indicate that

H3 receptor may play an essential role in modulating the activity of both thalamic projection neurons located in this area and the neurons of other brain areas that project to the midline area of thalamus, such as the cerebral cortex. H3 receptor mRNA expression detected by probe A was also higher in the anterior nuclei, the ones that represent the hypothalamic relay to the cerebral cortex from the mammillary nuclei. They are also considered as thalamic targets of the feedbacks from the hippocampal formation because of their bilateral connections with the subiculum (Steriade et

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Fig. 7. Changes of H3 receptor binding in rat thalamus after KA injection. (A, D, G, J) H3 receptor binding patterns in the control thalamus. (B) H3 receptor binding in the thalamus 12 h after KA injection. Re is indicated by the arrow. (E) H3 receptor binding in the thalamus 72 h after KA injection. LD, iml, Po, VPM, and VPL are indicated by the arrows. (H) H3 receptor binding in the thalamus 72 h after KA injection. LP, Po, VPM, DLG, and VLG are indicated by the arrows. (K) H3 receptor binding in MG 72 h after KA injection. The MG is indicated by the arrow. (C, F, I, L) The schematic figures show the most important landmark sites in the thalamus. The distances from bregma (according to the atlas of Paxinos and Watson, 1997) are: AYC, 2.80 mm; DYF, 3.30Y3.60 mm; GYI, 4.52Y4.80 mm; JYL, 6.04Y6.30 mm. (M) Relative binding levels based on the quantification are presented as means T SE. The average binding levels of the controls are set as 100% and presented by the open bars. The relative binding levels in these nuclei of KA-treated rats compared to the controls are presented by the filled bars. The statistical significance obtained from one-way ANOVA (Bonferroni’s multiple comparison test) is indicated by asterisks (*P G 0.05; **P G 0.01; ***P G 0.001). Scale bar: 3 mm.

al., 1997). The relatively higher H3 receptor mRNA expression level detected by probe A in those anterior nuclei indicates that the H3A and/or H3D isoforms modulate

the hypothalamo-cortical projections or might be involved in the thalamo-hippocampal connections. The mRNA expression and receptor binding patterns of H1 and H3

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receptors suggest the involvement of histamine in thalamic functions via these two receptors, especially in the synchronization of cortico-thalamo-limbic activities. In addition, H1 receptor mRNA expression was highest in Rt and ZI, the nuclei that contain GABAergic neurons and are important in regulating the activity of dorsal thalamus. However, H1 receptor binding was surprisingly low in these nuclei. The discrepancy is difficult to explain considering the knowledge of H1 receptor we have so far.

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controls the actual receptor binding sites on the nerve cell membrane (Marchese et al., 2003). In this way, any subtle or abrupt changes required by the environment can be met. That might as well explain the increase of H1 receptor mRNA expression in MG 24 h after KA injection without any subsequent elevation of H1 receptor binding levels in this nucleus. It is also possible that H1 receptors locate on the axonal terminals of the reticular neurons that mostly project to the dorsal thalamus since sometimes axons can be postsynaptic (Sherman and Guillery, 2001).

Down-regulation of mRNA expression and radioligand binding levels of H1 and H3 receptors after KA administration

Possible compensatory roles of H1 and H3 receptors after KA administration

Decreases in mRNA expression levels of the H1 receptor and the H3A and H3D isoforms were seen in MD and the midline thalamic areas such as PV, CM, and Re after KA injection. In line with a previous report that intense neuronal death in MD and in most of the midline areas appeared shortly after KA administration (Schwob et al., 1980), the decreased expression level in these areas is probably caused by cell loss. The H3 receptor mRNA expression detected by probe A decreased in Re shortly after KA injection (6 h). Re provides the principal thalamic projections to the subiculum and field CA1 of the hippocampus, and to the entorhinal and perirhinal areas (reviewed by Jones, 1985, 1998). A significant decrease of the H3 receptor radioligand binding in the entorhinal and perirhinal areas was found to start from 6 h after KA injection and last until the 1 w time point (data not shown). The decrease of H3 receptor expression detected by probe A in the thalamus might contribute to the decreased H3 receptor binding level in these parahippocampal cortical areas. Vice versa, H3 receptor binding decreased significantly in Re at the 12-h time point after KA injection compared to the controls. This resulted probably in part from the decreased H3 receptor mRNA expression detected by probe A in this nucleus. The decrease is also likely in part due to the cell loss in the amygdala, a limbic area that sends projections to Re. On the other hand, decreased H1 receptor mRNA expression appeared in Rt 12 h after KA injection, whereas no significant change of H1 receptor binding was found since the binding level in this nucleus was originally very low in the control animals. No obvious neuronal death in Rt has been described after KA administration (Schwob et al., 1980). Thus, the down-regulation of the H1 receptor mRNA expression in Rt is not likely caused by the cell loss, and it does not affect the H1 receptor binding level in this nucleus either. The significance of this change is difficult to explain. It is possible that the H1 receptor in this nucleus has very low affinity to the ligand we used in this study, or the receptor mRNA is not translated. Another possible mechanism is that the synthesized G-protein coupled receptors are not constantly present on the neuronal membranes. Instead, there may exist a robust recruitment system that circulates the receptor between compartments of the cell and

Despite the decreased H1 receptor mRNA expression level shortly after KA injection, higher H1 receptor binding level was displayed in PV 24 h after KA injection, while unchanged at the other time points. Since no corresponding increase of the H1 receptor mRNA expression in this area was seen, the increased H1 receptor binding might be a result of increased dendritic spine formation. It has been reported that in the granule cells of mouse dentate gyrus, the number of dendritic spines increases after KA-induced lesion (Suzuki et al., 1997). It is possible that reformation of the dendritic trees of neurons also occur in the thalamic neurons of PV that express H1 receptors. Hence, despite the neuronal loss in this area, the increased number of dendritic terminals with H1 receptors results in an increase of total H1 receptor binding sites. Similarly, H1 receptor mRNA expression decreased in MD, CM, and Re, the thalamic nuclei where massive neuronal loss occurred after KA administration. However, the H1 receptor binding level was unaffected in these areas except for a decrease in Re at the 24-h time point. The up-regulation or maintenance of H1 receptor binding level in this area also indicates the potential functional significance of H1 receptor under the pathological conditions. Three days after KA injection, significant increases in H3 receptor radioligand binding were found in iml, CM, LD, LP, Po, VPM, VPL, DLG, and MG. Both LP and Po receive inputs from the pretectum and superior colliculus of the midbrain and are parts of the visuomotor pathway (Linke et al., 1999; Schobber, 1981; Taylor et al., 1986; Thompson and Robertson, 1987), while VPM and VPL are the principle somatosensory relays that receive inputs from the principal trigeminal and dorsal column nuclei, respectively (summarized by Jones, 1998). The elevated H3 receptor radioligand binding level in these areas suggests the involvement of H3 receptor in the visuomotor and somatosensory modulation after KA administration. Increased H3 receptor binding level was also found in iml, the thalamic region that receives diverse projections from the globus pallidus (Hendry et al., 1979), deep cerebellar nuclei (Faull and Carman, 1978), frontal eye field, parietal cortex (for review, see Schlag and Schlag-Rey, 1989), midbrain (Graham and Berman, 1981), substantia nigra

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(Hendry et al., 1979), as well as the reticular formation of the mesencephalon, pons and medulla (Loewy et al., 1981). Any changes in H3 receptor mRNA expression in these regions may cause a secondary change of binding in iml. This area participates in neural circuits underlying attention and gaze control (for a review, see Schlag and Schlag-Rey, 1989). Moreover, it is an important component of the nonspecific thalamo-cortico-thalamic circuit that is crucial in the network oscillation, and is involved in cognition (Bogosslavsky et al., 1986; Mills and Swanson, 1978; Steriade et al., 1997). Our result shows that H3 receptor changes in these systems shortly after the KA injection. Major increases of H3 receptor mRNA expression detected by probe A were found in VPL, VPM, and Po 1 week after KA injection and lasted till the last time point (4 weeks). These structures participate in the generation of epileptiform activities (reviewed by Huguenard and Prince, 1997). Both ventral posterior and posterior thalamic regions project to the parietal and temporal cortical areas, and lesions in VPL tend to suppress the motor seizure activity in monkeys (Mondragon and Lamarche, 1990). The increased H3 receptor mRNA expression detected by probe A in these areas may contribute to the inhibition of excitatory outflow to the parietal and temporal cortex, which correlates well with our finding that H3 receptor binding level significantly increased in the secondary somatosensory cortex at 1 w time point (data not shown), and thus play an anti-seizure role. Moreover, it has been demonstrated that neuronal necrosis occurs in VPL and VPM after long periods of status epilepticus as a consequence of the prolonged neuronal hyperactivity (reviewed by Ingvar, 1986). A significant, transient and short-lasting increase of H3 receptor mRNA has been reported in the CA3 field of the hippocampus 6Y24 h and in the CA1 field 12Y24 h after systemic KA using probe A (Lintunen et al., 2001a), suggesting that the H3 receptor isoforms with full-length IC3 may indeed be an important indicator of damage. H3 receptor, especially the H3A isoform, can activate the p42/44 MAPK pathway (Drutel et al., 2001). MAPK activation may activate CREB, an important protein in neuronal survival (Tanaka, 2001; Walton and Dragunow, 2000). In the case of excitotoxicity induced by toluene administration, there is a transient activation of p42/44 MAPK in cultured rat cortical astrocytes that is shown to play a protective role (Lin, 2002). Similarly, quinolinic acid-induced excitotoxicity leads to p42/44 MAPK over-expression in the rat cortex and correlates well with cell survival (Ferrer et al., 2001). In line with the observation that H3 receptor binding level increased in VPM, VPL, and the secondary somatosensory cortex (where they send projections to) at the same time (1 w after KA injection), it is very possible that the increases of H3 receptor mRNA expression detected by probe A lead to MAPK stimulation in VPL and VPM, and thus protect the neurons in these nuclei from neuronal death caused by longterm status epilepticus. Besides, H3 receptor activates PKA (Drutel et al., 2001), which is also able to prevent apoptosis

possibly via activation of Bad (Cross et al., 2000). However, no increase in H3 receptor binding level was seen in VPM, VPL, and the secondary somatosensory cortex at the 4 w time point. This does not correlate to the high H3 receptor mRNA expression detected by probe A in these two nuclei at the 4 w time point. Apparently, this H3 mRNA expression does not contribute to increased cell surface H3 receptors capable of ligand binding. The detailed signaling pathways of H3 receptor are still under investigation and other messengers may also be involved. Moreover, novel tools to detect receptor isoform proteins would be needed to gain information on the dynamics of functional H3 receptor isoforms. It would be important to develop drugs that specifically bind to the H3 receptor isoforms with full-length IC3 to see if these may affect seizure development and damage associated with limbic seizures. The overall effects of such drugs cannot be deduced from this study because the H3 receptors are expressed on a number of different neurons involved in the seizure circuits.

Conclusions H1 receptor and H3 receptor isoforms are expressed and binding sites are distributed in the thalamic areas crucial for the limbic-thalamo-cortical network synchronization as well as in the visual and auditory pathways. The transient impairment of these receptor systems in the midline thalamic area at the early stage after KA administration is probably due to the neuronal death. The early increase in H3 receptor binding in the thalamus is probably due to increased H3 receptor mRNA level in the afferent cortical and subcortical systems. However, the elevated H3 receptor binding in the intralaminar area, and the late robust changes of H3 receptor mRNA expression detected by probe A in the sensory and motor relays suggest neuroprotective and compensatory mechanisms through H3 receptor activation during KA-induced seizures.

Acknowledgments This work was supported by the Academy of Finland, Alcohol Research Foundation, Magnus Ehrnrooth Foundation and Paulo Foundation.

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