Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome

Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome

Brain Research 749 Ž1997. 238–244 Research report Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome Mara ...

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Brain Research 749 Ž1997. 238–244

Research report

Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome Mara Dierssen, Iria F. Vallina, Carmela Baamonde, Salvador Garcıa-Calatayud, ´ ) M. Angeles Lumbreras, Jesus Florez ´ ´ Department of Physiology and Pharmacology, Faculty of Medicine, UniÕersity of Cantabria, 39011 Santander, Spain Accepted 24 September 1996

Abstract Mice with segmental trisomy 16 ŽTs65Dn. which have triplication of a region of mouse chromosome 16 homologous to the Down syndrome critical region in human chromosome 21, are used as a model for Down syndrome. Functioning of the central b-noradrenergic transmission was studied in Ts65Dn mice. Binding analysis in cerebral cortex revealed no change in the number of b-adrenoceptors and a slight reduction of affinity. The b-adrenoceptor transduction was assessed by analyzing cAMP formation in the cerebral cortex, hippocampus and cerebellar cortex under basal conditions and after stimulation with isoprenaline and forskolin. Basal production of cAMP was significantly reduced in hippocampus and cerebellar cortex of Ts65Dn mice compared to control, but not in cerebellum. After phosphodiesterase inhibition, net increments in cAMP accumulation were similar in both groups of mice. Stimulation of cAMP production by isoprenaline Ž10 m M. and forskolin Ž10 m M. was much higher in hippocampus than in cerebral cortex of either group. In both areas, but not in cerebellum, the stimulatory responses were consistently and significantly smaller in Ts65Dn than in control mice. Concentration–response curves for isoprenaline and forskolin were generated in the cerebral cortex. Emax responses were lower in trisomic than in control mice; however, in Ts65Dn mice the slope of the response curve to isoprenaline was markedly depressed whereas that to forskolin was similar to control. It is concluded that Ts65Dn mice show severe deficiencies in the synaptic transmission of the central b-noradrenergic system, which are selective for specific brain areas. q 1997 Elsevier Science B.V. All rights reserved. Keywords: Down syndrome; Trisomic mouse; b-Adrenoceptor; Hippocampus; Cerebral cortex; Cerebellum

1. Introduction Trisomy 21 or Down syndrome ŽDS. is the most common form of mental retardation with a known genetic cause. A number of pathological abnormalities have been found in several areas of the DS brain, including the frontal cortex, hippocampus and cerebellum, along with diffuse cerebrocortical pathology that includes disturbances in neuronal density, dendritic spines development and synaptic functioning w1,10,13,18,36x. Indeed, some of these abnormalities appear to be relevant to mental retardation. In addition, DS is associated with defects of heart and gut development, infertility, immunodeficiencies, facial dismorphology and an increased risk of leukaemia. A thorough analysis of the developmental consequences of

) Corresponding author. Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Avenida Herrera Oria, srn, 39011 Santander, Spain. Fax: q34 Ž42. 201903.

DS requires an animal model that can provide access to cells and tissues from all developmental stages. Mice that are trisomic for chromosome 16, which shares a large region of genetic homology with human chromosome 21, have been widely used as an animal model for human DS w5,9,11,27x. However, trisomy for the whole chromosome 16 is incompatible with post-natal survival, so a new mouse model has been developed using a reciprocal translocation containing the distal end of mouse chromosome 16 w6x. These mice are trisomic for genes corresponding to those on human chromosome 21q21-22.3, known as the DS ‘critical region’ wTs Ž17 16 .65Dnx. Although this model does not have all the features characteristic of DS, the mice survive to adulthood and they may be useful to study behavioral functions and other features that develop later in life. Preliminary characterization of segmentally trisomic Ts65Dn has revealed some consistent phenotypic abnormalities, such as development delay, hyperactivity, early onset obesity and muscular trembling w6,16,29x, some of

0006-8993r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 0 0 6 - 8 9 9 3 Ž 9 6 . 0 1 1 7 3 - 0

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which are shared with DS. In addition, our previous result demonstrate behavioral abnormalities and alterations in learning processes consistent with impaired performance of individuals with DS w12x. However, no neurochemical data in this model have been reported. As a first approach, we have studied the function of the central noradrenergic system which is involved in attentional and cognitive processes, and has been known to be sensitive in early developmental stages. The density and affinity of the b-adrenoceptors have been determined in mice cerebral cortex by a saturation binding method. In addition, the functioning of the system has been assessed by analyzing cAMP formation under both basal and stimulated conditions in the cerebral cortex, hippocampus and cerebellum.

2. Materials and methods 2.1. Animals Ts65Dn Ž n s 7. Ž20–28 weeks old. were used in the saturation binding study. All mice were supplied by the Jackson Laboratory ŽBar Harbor, ME, USA.. They were housed individually and maintained with food and water freely available, with a 12-h light–dark cycle Ž08:00 light on. and controlled temperature Ž22 " 28C.. 2.2. cAMP assay cAMP levels were measured according to Brown w2x with slight modifications. Briefly, animals were killed by decapitation, the brains removed and cerebral cortex, hippocampus and cerebellum quickly dissected on ice. Tissues were cross-chopped into 350 = 350-m m slices ŽMcIlwain tissue chopper., placed in separate glass tubes containing Krebs solution pH s 7.4 of the following composition Žin mM.: NaCl 117; KCl 4.96; CaCl 2 2.47; KH 2 PO4 1.16; MgSO4 1.18; NaHCO 3 24.3; and glucose 6.9. The solution was maintained at 37 " 0.58C and continuously gassed with 95% O 2 –5% CO 2 mixture. Slices were separated by gentle vortexing and tissues washed by mild vacuum. The differential b-adrenoceptor response was studied in tissues incubated for 10 min with phenoxybenzamine 1 m M, dissolved in tartaric acid solution Ž0.2 mM., to ensure a-adrenoceptor blockade, and then washed 4 = with mild vacuum for complete withdrawing. Thereafter, incubations in Krebs-Ringer medium were carried out for a further 20 min at 378C in a shaking water bath. 2.3. Drug treatment of slices At the end of this preliminary incubation stage, aliquots Ž0.5 ml slicerbuffer solution. from each pooled sample were transferred to glass tubes and 3-isobutyl-1-methylxanthine ŽIBMX. Ž1 mM., isoprenaline Ž10 m M. or vehicle Ž50 m l. were added and incubated for 10 min. Ascorbic acid Ž0.2 mg P mly1 . was present where necessary to pre-

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vent isoprenaline oxidation. To analyze the profile of the isoprenaline-stimulated cAMP accumulation, concentration–response curves for isoprenaline Ž0.1 m M to 0.1 mM. were generated. In these experiments, IBMX 1 mM was used to prevent cAMP breakdown. In all experiments, the reaction was terminated and tissue cAMP released by heating the tubes for 10 min at 1008C. Thereafter, tissue debris was removed by centrifugation Ž1500 = g for 15 min at 48C.. Protein content was determined in the pellet with the method of Lowry et al. w21x using BSA as a standard. The cAMP content was determined in 100 m l of the supernatant by a sensitive protein assay w33x. The assay is based on competition between unlabelled cAMP and a fixed quantity of w 3 HxcAMP Ž9.1 mCirmg. for binding to a protein extracted from bovine muscle that has high specificity and affinity for cAMP. Separation of the protein-bound cAMP from the unbound nucleotide is achieved by adsorption of the free nucleotide on the coated charcoal, stirred continuously to ensure uniform mixture and followed by centrifugation. An aliquot of the supernatant is then removed for liquid scintillation counting. 2.4. Binding studies Membrane homogenates were separated according to the method of Duncan et al. w8x with minor modifications. Briefly, animals were killed by decapitation, the brains removed and cerebral cortex quickly dissected on ice. Cerebral cortex was minced and homogenized in ice-cold 50 mM Tris-HCl solution pH s 7.8 Ž1r30 wrv. in a pre-cooled polytron tissue homogenizer Ž3 = 10-s bursts.. The homogenate was centrifugated at 32 000 = g for 30 min at 48C. Pellets were re-suspended by hand with a glass-Teflon homogenizer. This procedure was repeated twice. The final pellet was re-suspended in incubation buffer to adjust the protein content to f 500 m g. Aliquots of 0.15 ml of the membrane preparation were incubated in a total volume of 0.2 ml with w 3 HxCGP12-177 Ž0.025–1.6 nM in saturation binding studies. for 90 min at 258C. Incubation was terminated by rapid vacuum filtration ŽBrandel M24R Cell Harvester. through Whatman GFrB filters. The tubes were rinsed 2 = with 5 ml of ice-cold incubation buffer wich was subsequently filtered. Propranolol Ž1 m M. was used to define non-specific binding wich usually amounted to 40–50% of total binding Žat w 3 HxCGP12-177 concentration close to the K d value.. The protein content was determined by the method of Lowry et al. w21x. The radioactivity retained on the filters was determined by liquid scintillation spectrometry with a counting efficiency of 60%. Data derived from radioligand studies were analyzed by computerized iterative non-linear least squares regression using LIGAND program w25x. Assays were carried out in duplicate and data were expressed as the mean " S.E.M. values of six experiments. The statistic significance of differences between mean data was evaluated by Student’s t-test. The level of significance was set at P - 0.05.

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2.5. Chemicals IBMX, isoprenaline, adenosine 3X , 5X-cyclic monophosphate, noradrenaline and forskolin were supplied by Sigma ŽSt. Louis, MO, USA., phenoxybenzamine was obtained from Smith Kline and French Laboratories ŽPhiladelphia, PA, USA., bromo-acetyl-alprenolol menthane from Research Biochemical Incorporated, w 3 HxcAMP assay system and w 3 HxCGP12-177 were supplied by Amersham Life Science ŽBuckinghamshire, UK.. 2.6. Statistics cAMP were calculated as pmol cAMP formed per mg protein. Data are expressed as mean " S.E.M. values of data of 3 independent experiments performed in triplicate. Significance of the overall effect of the treatment was determined by one-way analysis of variance ŽANOVA.. Comparisons between groups were calculated using the Student’s t-test Žtwo-tailed.. In some cases, the net increase was calculated; for this purpose, basal activity was subtracted from the total activity Žsee Section 3.. Concentration–response curves were fitted to a four parameter logistic function by means of non-linear regression analysis, using an iterative curve-fitting program which gave estimates of the maximum response, EC 50 , and slope of the curve. Statistical analysis was done with the computer program GraphPad ŽGraphPad ISI, Philadelphia, PA, USA..

3. Results 3.1. Binding experiments Crude membrane preparations obtained from seven brain cortices of control mice and seven of Ts65Dn mice were incubated with w 3 H xCGP12-177. The binding of

Fig. 2. A: cAMP levels in basal conditions ŽKrebs. and, after inhibition of phosphodiesterase ŽIBMX., in control Žopen bars. and Ts65Dn Žhatched bars. in cerebral cortex ŽCx., hippocampus ŽHc. and cerebellum ŽCb.. Values are expressed as mean"S.E.M. B: cAMP accumulation under conditions of phosphodiesterase inhibition ŽIBMX. and, after incubation with 10 m M isoprenaline ŽIso. and 10 m M forskolin ŽFk., in the cerebral cortex ŽCx., hippocampus ŽHc. and cerebellum ŽCb. of control Žopen bars. and Ts65Dn mice Žhatched bars.. Values are given as mean"S.E.M.

w 3 HxCGP12-177 to mice cerebral cortex homogenates was monophasic and clearly saturable; there was a slight not significant decrease in the Bmax value in Ts65Dn mice Ž96.47 " 11.71 vs. 80.62 " 1.67 fmol P mgy1 protein.. The Scatchard plot of the data was linear in both groups with a K d value of 1.29 " 0.37 nM in control group and 2.08 " 0.37 nM in Ts65Dn mice Ž P - 0.05, one-tailed., indicating that, although there were not differences in w 3 HxCGP12177-binding sites, the affinity of b-adrenoceptors in cerebral cortex of Ts65Dn mice was decreased compared to control ŽFig. 1.. Fig. 1. Scatchard analysis of b-adrenoceptor saturation studies with w 3 HxCGP12-177 in mouse brain cortex from a representative experiment. `Control mouse, vTs65Dn mouse.

3.1.1. Basal leÕel of cAMP Basal levels of cAMP were significantly lower in Ts65Dn mice vs. controls in two cerebral regions studied

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Fig. 3. A: concentration–response curve for the accumulation of cAMP after incubation with increasing concentrations of isoprenaline Ž0.1 m M–0.1 mM. in cerebral cortex of Ts65Dn Žblack circles. and control mice Žwhite circles.. Values are given as mean " S.E.M. B: concentration–response curve for the accumulation of cAMP after incubation with increasing concentrations of forskolin Ž0.1 m M–0.1 mM. in cerebral cortex of Ts65Dn Žblack circles. and control mice Žwhite circles.. Values are given as mean " S.E.M.

ŽFig. 2A.. The hippocampus presented the most marked difference in basal production of cAMP Ž P - 0.001., although they were also significant in cerebral cortex Ž P 0.05.. In contrast, basal levels of the second messenger in cerebellum of Ts65Dn were not modified or even showed a tendency to increase that was not statistically significant. In conditions of inhibition of phosphodiesterase activity by addition of IBMX Ž1 mM. to the incubation medium, cAMP accumulation was increased with respect to basal levels in control and Ts65Dn mice Ž P - 0.05. in the three areas studied ŽFig. 2A.. In these experiments, although the raw data were higher in controls Ž P - 0.01. than in trisomic mice, the net increase was similar in both groups in cerebral cortex Ž% in trisomic vs. % in controls, N.S... Finally, when the production of cAMP was induced by stimulation at the receptor level with isoprenaline ŽFig. 2B., the levels attained were higher in control mice than in Ts65Dn, the differences being statistically significant Ž t s 41.24, P - 0.001.. The net increase in cAMP production with respect to basal levels was much higher in hippocampus than in cerebral cortex, both in controls Ž P - 0.01. and in Ts65Dn Ž P s 0.026.. In hippocampus, the stimulation induced by isoprenaline was lower in Ts65Dn than in controls, the difference being statistically significant Ž t s 5.18, P - 0.05.. Finally, in cerebellum the increase in cAMP induced by isoprenaline was similar in control and Ts65Dn mice Ž P s 0.32. ŽFig. 2B.. 3.1.2. Concentration–response curÕe for isoprenaline In an attempt to evaluate the responsiveness of the cAMP-generating system linked to further b-adrenoceptor stimulation, brain slices were incubated with increasing concentrations of isoprenaline Ž0.1 m M–0.1 mM. in

Ts65Dn and control mice ŽFig. 3A.. This study was performed only in cerebral cortex due to lower availability of tissues in the other structures. In the control mice, isoprenaline stimulated in a concentration-dependent manner the accumulation of cAMP Ž F s 4939.8, P - 0.01.; the maximum effect attained Ž Emax s 882.5 " 0.4 pmol cAMPP mgy1 protein. was significantly higher than in Ts65Dn mice Ž Emax s 303.2 " 14.0 pmol cAMPP mgy1 protein. Ž P - 0.001.. Furthermore, in the trisomic mice isoprenaline was not able to increase cAMP production to the same extent as in controls, so that a shift to the right and a flattening of the concentration–response curve were observed in the trisomic mice compared to that of the controls Ž F s 9.25, P - 0.05.. 3.1.3. Concentration–response curÕe for forskolin Further assessment of the cAMP-generating system was performed by analyzing the response to direct stimulation of the adenylyl cyclase with forskolin. In hippocampus and cerebellum, a single sub-maximal concentration of forskolin Ž10 m M. was tested, whereas in cerebral cortex a concentration–response curve was performed by adding increasing concentrations of forskolin Ž0.1 m M–0.1 mM.. Incubation with forskolin Ž10 m M. induced a significant increase in cAMP levels with respect to basals in every region studied ŽFig. 2B., but the increment was smaller in trisomic mice than in controls, both in absolute values Ž P - 0.01. and when considering net increases Ž% trisomic vs. % controls, P - 0.05.. In hippocampus of Ts65Dn, the stimulation of the catalytic subunit induced a significant increase in cAMP levels Ž P - 0.05 with respect to basal levels., that was lower than in controls Ž P - 0.01. ŽFig. 2B.. In cerebellum, the increment was similar in both

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experimental groups although, in terms of net increase, the stimulation attained was higher in controls Ž P - 0.05. ŽFig. 2B.. In cerebral cortex, incubation with increasing concentrations of forskolin elicited a concentration-dependent increase in cAMP accumulation that was significant in both experimental groups Ž F s 306, P - 0.05 in Ts65Dn, F s 401.06, P - 0.01 in controls. ŽFig. 3B.. The Emax was 778.52 " 102 pmol cAMPP mgy1 protein in controls Ž183.8% of increase vs. basal values. and 454.38 " 52.4 pmol cAMPP mgy1 protein in Ts65Dn Ž P - 0.05., Ž227.8% increase vs. basal values., the differences in the net increase between both groups not being significant Ž t s 2.67, P s 0.11..

4. Discussion The present experiments extend our preliminary results w7x and reveal consistent disturbances in the primary biochemical response elicited by the activation of b-adrenoceptors in specific brain regions of the Ts65Dn mice. Ligand-binding studies disclosed a reduced affinity of the receptor for the ligand that may partially account for the reduced cAMP generation. On the other hand, the density of b-adrenoceptors does not seem to contribute to such alteration because Bmax was very slightly and unsignificantly reduced, although preliminary autoradiographic studies show a moderate decrease of b-adrenoceptors density in some cortical and hippocampal layers Žunpublished observations.. The severity of the deficits detected in cAMP production suggests the existence of abnormalities in the function of the enzyme system. The first series of experiments demonstrated an impaired basal activity of adenylyl cyclase activity in cerebral cortex and hippocampus of the segmental trisomy mice. On the other hand, phosphodiesterase activity seemed to be normal in trisomic compared to control mice since the cAMP accumulation was comparable in both groups after inhibition of cAMP degradation. In addition, our experiments showed significant abnormalities in the noradrenergic receptor-mediated biochemical response in hippocampus and cerebral cortex but not in cerebellum of Ts65Dn mice. The stimulating effect of isoprenaline was much less effective for generating cAMP in the trisomic model, the impairment being more intense in the hippocampus. Decreased sympathetic function has been suggested to be a feature of DS individuals, with possible consequences for their normal development. Previous studies demonstrated reductions in plasma norepinephrine levels in DS individuals w20x, but its urinary metabolite 3methoxy-4-hydroxyphenylglycerol was not altered w22x. McSwigan et al. w24x detected altered receptor-mediated responses, the accumulation of cAMP being increased in fibroblasts of individuals with DS after exposure to badrenergic agonists but not after cholera toxin or prostaglandin E 1. Studies on CNS noradrenergic transmission in

infants or young individuals with DS are very scarce because most reports are concerned with the aging brain where abundant Alzheimer-like pathology is added to early induced pathogenic alteration w26,35x. In an infant with DS, McGeer et al. w23x described incresed concentrations of norepinephrine in putamen and globus pallidus, but decreased in the other brain areas. In other genetic models for DS, such as the trisomy 16 mouse ŽTs16., alterations in the catecholaminergic systems have also been observed w27x. Consistent reductions in cortical dopamine and in cortical and brainstem norepinephrine have been reported w32x. These observations were later extended to trisomy 19 w31x. In addition, disturbances in other pre-synaptic markers have been detected in animal and cellular models. A reduction in the specific activity of dopamine b-hydroxylase and tyrosine hydroxylase was reported in Ts16 mice w28,32x. However, preliminary immunohistochemical studies in our laboratory have not shown differences in the content of tyrosine hydroxylase in the brainstem of control and Ts65Dn mice. The norepinephrine uptake was inhibited in Ts16 chromaffin cells w19x as well as chromaffin granules of PC12 rat cells transfected with CurZn superoxide dismutase ŽSOD. gene and in chromaffin cells of transgenic mice overexpressing CurZn SOD gen w15x. The present results confirm the existence of an alteration in the neurochemical features of the catecholaminergic system in a genetic model of DS as is the partial trisomy Ts65Dn, extending the previous information with additional data about the post-synaptic elements in the neurochemical chain. In our experimental series, the impaired post-receptor response in the cortical and hippocampal neurones was not related to alterations in b-adrenoceptor densities. This is not surprising since the gene encoding this receptor is located on HSA5, and not in HSA21. However, the alterated affinity could reveal deficiencies in the transduction chain either at the level of G-proteins or in the regulatory mechanisms involved in the inactivation of the receptor, such as the b-adrenoceptor kinase. Specific studies will be needed to confirm this point. Our findings also demonstrate that the impairment of the biochemical response to the activation of b-adrenoceptors in the brain of partially trisomic mice could be in part produced by an alteration in the activity of the catalytic subunit of the adenylyl cyclase. When cAMP accumulation was stimulated by the addition of the incubation medium of forskolin, which activates directly this subunit of the enzyme, the net percentage increase was similar in Ts65Dn and in control mice, but the concentration–response curve for forskolin was shifted to the right in the trisomic mice. However, the impairment in adenylyl cyclase activity seems to be region-specific, thereby suggesting that different isoforms of the enzyme may be differentially affected by the genetic condition. Adenylate cyclase activity has been proposed to be critical in the formation of memory. It has been suggested

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that short-term memory is the result of stimulus convergence on adenylate cyclase inducing the cAMP-dependent phosphorylation of substrate proteins, leading to an enhanced synaptic transmission w3,14x. Recent evidence also implicates this second messenger in the formation of more stable memories since neurochemical and morphological modifications are observed after manipulations, such as the training procedure in passive and active avoidance tests w17,30x. Therefore, genetic alterations that have consequences on the functioning of this second messenger may account for the impairment of information processing detected in the Ts65Dn model w4,12,29x. In this regard, it must be pointed out that specific learning deficits associated to hippocampal function, such as the spatial cognitive system, typically emerge in individuals with DS w34x. In conclusion, our study demonstrates the presence of severe alterations in the cAMP pathway in cerebral cortex and hippocampus of Ts65Dn mice, an effect that may account for the behavioral alterations observed in this murine model. These deficits affect the efficiency of the second messenger cascade, therefore having consequences on the primary biochemical response of the noradrenergic system in some brain regions. Other factors in the cellular regulatory system may be affected by the genetic condition as well since the affinity of b-adrenoceptors is lower in the trisomic animal.

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Acknowledgements

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The work was supported by Ramon ´ Areces Foundation, Marcelino Botın ´ Foundation and DGICYT Grant PC 941063 from the Spanish Ministry of Education. I.F.V. received a fellowship from Real Patronato de Prevencion ´ y Atencion ´ a Personas con Minusvalıas. ´ The technical assistance of Marıa ´ Jose´ Rozas is gratefully acknowledged.

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