Serotonin transporter deficiency in rats contributes to impaired object memory

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Genes, Brain and Behavior (2009) 8: 829–834

© 2009 The Authors Journal compilation © 2009 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society

Serotonin transporter deficiency in rats contributes to impaired object memory J. D. A. Olivier∗,† , L. A. W. Jans‡ , A. Blokland‡ , N. J. Broers§ , J. R. Homberg† , B. A. Ellenbroek¶ and A. R. Cools† † Donders Institute for Brain, Cognition and Behaviour,

Department of Cognitive Neuroscience, Molecular Neurobiology and Psychoneuropharmacology, Radboud University Nijmegen Medical Centre, Nijmegen ‡ Department of Neuropsychology & Psychopharmacology, Faculty of Psychology Maastricht University, and § Department of Methodology and Statistics, Maastricht University, Maastricht, The Netherlands, and ¶ Department of Neuropharmacology, Evotec, Hamburg, Germany *Corresponding author: J. D. A. Olivier, Radboud University Nijmegen Medical Center, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands. E-mail: [email protected]

Serotonin is well known for its role in affection, but less known for its role in cognition. The serotonin transporter (SERT) has an essential role in serotonergic neurotransmission as it determines the magnitude and duration of the serotonin signal in the synaptic cleft. There is evidence to suggest that homozygous SERT knockout rats (SERT−/− ), as well as humans with the short SERT allele, show stronger cognitive effects than wild-type control rats (SERT+/+ ) and humans with the long SERT allele after acute tryptophan depletion. In rats, SERT genotype is known to affect brain serotonin levels, with SERT−/− rats having lower intracellular basal serotonin levels than wild-type rats in several brain areas. In the present study, it was investigated whether SERT genotype affects memory performance in an object recognition task with different intertrial intervals. SERT−/− , heterozygous SERT knockout (SERT+/− ) and SERT+/+ rats were tested in an object recognition test applying an inter-trial interval of 2, 4 and 8 h. SERT−/− and SERT+/− rats showed impaired object memory with an 8 h inter-trial interval, whereas SERT+/+ rats showed intact object memory with this inter-trial interval. Although brain serotonin levels cannot fully explain the SERT genotype effect on object memory in rats, these results do indicate that serotonin is an important player in object memory in rats, and that lower intracellular serotonin levels lead to enhanced memory loss. Given its resemblance with the human SERTlinked polymorphic region and propensity to develop depression-like symptoms, our findings may contribute to further understanding of mechanisms underlying cognitive deficits in depression. doi: 10.1111/j.1601-183X.2009.00530.x

Keywords: Knockout, memory, object recognition, rat, serotonin transporter

Received 10 March 2009, revised 15 May 2009; 23 July 2009, accepted for publication 28 July 2009

Serotonin plays an important role in the modulation of many physiological and behavioral processes (Heninger 1995). Serotonergic neurotransmission is mainly regulated by the serotonin transporter (SERT), which determines the magnitude and duration of the serotonin signal in the synaptic cleft. The SERT is of interest in many research areas as it is the target for selective serotonin reuptake inhibitors (Meyer et al . 2004; Murphy et al . 1998; Suhara et al . 2003; Voineskos et al . 2007), which have therapeutic efficacy in several neuropsychiatric disorders (for review, see Vaswani et al . 2003). Humans exhibit a SERT-linked polymorphic region (5HTTLPR) with two functional variants: the short (s) form and the long (l) form (Greenberg et al . 1999; Heils et al . 1996; Lesch et al . 1996). The s form of this variant is less active, resulting in reduced transcriptional efficiency of the SERT gene, decreased SERT expression and reduced serotonin uptake compared with the l variant (Greenberg et al . 1999; Heils et al . 1996, 1997; Lesch et al . 1996). Reduced SERT expression has been associated with anxiety- and depression-related personality traits, increased vulnerability to tryptophan depletion (Firk & Markus 2009; Neumeister et al . 2002; Roiser et al . 2006) and abnormal emotional processing (Hariri et al . 2002; Marsh et al . 2006; Neumeister et al . 2002). Beyond affection, several lines of evidence point out that serotonin modulates learning and memory processes, especially the consolidation of new information into long-term memory (Buhot et al . 2000). Memory is a multifaceted cognitive function, and the role of serotonin in this process has been shown in both humans and animals (Buhot 1997; Buhot et al . 2000; Meneses 1999; Riedel et al . 1999; Schmitt et al . 2000). The involvement of SERT in memory is not well known, but it has been shown that the 5-HTTLPR genotype has an effect on recognition memory (Roiser et al . 2007). However, there are also studies that show no 5-HTTPLR genotype difference in memory (Reneman et al . 2006). Applying acute tryptophan depletion (ATD) to temporarily lower serotonin has been shown to have a negative effect on memory in humans (Park et al . 1994; Riedel et al . 1999; Sambeth et al . 2007; Schmitt et al . 2000) and rats (Jans et al . 2007; Lieben et al . 2004b; Rutten et al . 2007). In a rat model for decreased intracellular serotonin levels, we recently showed that homozygous SERT knockout rat (SERT−/− ), heterozygous SERT knockout rat (SERT+/− )


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and wild-type control rat (SERT+/+ ) all have good object recognition memory when a 1-h inter-trial interval (ITI) is used (Olivier et al . 2008b). The absence of impaired object recognition in SERT−/ – rats is likely because of the short ITI that was used in the previous study. By increasing the ITI, object recognition is expected to deteriorate, and when the interval is long enough, rats will show no object recognition. Therefore, in the present study we investigated whether SERT−/− , SERT+/− and SERT+/+ rats are differently affected by an increasing ITI in the object recognition test. All genotypes were tested with an interval of 2, 4 and 8 h between trials. SERT+/ – and SERT−/ – rats were hypothesized to show stronger deterioration of object recognition with increasing ITIs than SERT+/+ rats.

Materials and Methods Animals The SERT knockout rat (Slc6a41Hubr ) has been generated (Smits et al . 2004, 2006), bred and reared in the Central Animal Laboratory of the Radboud University of Nijmegen. Experimental animals were derived from crossing SERT+/ – rats that were outcrossed for seven generations with wild-type Wistar rats to eliminate other possible ENU-induced background mutations. A total of 36 male SERT+/+ , SERT+/ – and SERT−/ – littermates (n = 12 per genotype; aged 20–25 weeks) were used in this experiment. After weaning at the age of 21 days, ear cuts were taken for genotyping. Genotyping was performed at the Hubrecht Institute (Utrecht, the Netherlands) and the procedure has been described elsewhere (Homberg et al . 2007a). During the experiment, all animals were individually housed in standard Macrolon® type 3 cages (42 × 26 × 20 cm) in temperaturecontrolled rooms (21 ± 1◦ C) with standard 12/12-h day/night-cycle (lights on at 0700 h) and food (Sniff, long cut pellet, Bio Services, Uden, The Netherlands) and water available ad libitum. Adequate measures were taken to minimize pain or discomfort of the animals. All experiments were carried out in accordance with the Guidelines laid down by the European Communities Council Directive of 24 November 1986 (86/609/EEC).

Object recognition task The object recognition task was performed as described elsewhere (Ennaceur & Delacour 1988; Olivier et al . 2008b; Prickaerts et al . 2002). The apparatus consisted of a square arena (100 × 100 × 40 cm), with an open top, dark walls and a dark floor. Testing was carried out in dimmed white light. We used four different sets of objects that could not be displaced by the rat. Each object was available in triplicate. The different objects were as follows: (1) a bowl with handle made of green china (maximal diameter 15 cm and a height of 9 cm), (2) a cubic box (12 × 12 × 7 cm) made of polyvinyl, with a pink topping, (3) a china trapezium cylinder (maximal diameter 12 cm and minimum diameter 10.5 cm) with a dish on top (diameter 12 cm) and (4) a brown tinned cylinder (diameter 9.5 cm and height 15 cm). One day preceding testing, the animals were adapted to the procedure, i.e. they were allowed to explore the apparatus (without any objects) for 3 min. After being adapted to the procedure, testing began. A test session comprised two 3-min trials with a 2, 4 or 8 h interval between trials. All rats were tested in all ITIs. Two objects were placed in a symmetrical position about 10 cm away from the black wall. A rat was always placed in the apparatus facing one corner, which was the same for all rats. During the first trial, the apparatus contained two identical objects. After the first exploration period, the rat was put back in its home cage. After 2, 4 or 8 h, the rat was put back in the apparatus for the second trial, but now with dissimilar objects, a familiar one and a new one. The duration of exploring each object in both trials was recorded manually on a personal computer. Exploration was defined as directing the nose


to the object at a distance of not more than 2 cm and/or touching the object with the nose. Sitting on the object was not considered as exploratory behavior. In order to avoid the presence of olfactory trails, the objects were thoroughly cleaned between trials with a 70% ethanol solution. Moreover, each object was available in triplicate so that none of the two objects from the first trial had to be used as the familiar object in the second trial. All combinations and locations of objects were used in a balanced manner to reduce potential biases because of preferences for particular locations or objects. In addition, the order of ITI was balanced. The basic measures in the object recognition task were the times spent by rats exploring an object during trial 1 and trial 2. The discrimination index d 2 [(exploration new object during trial 2–exploration familiar object during trial 2)/total exploration time during trial 2] was calculated for each treatment condition (Rutten et al . 2007). The d 2 is a relative index of discrimination between new and familiar object, because it corrects for total exploration time in trial 2 (see Sik et al . 2003). Rats that explored less than 1 s in any of the trials or explored only one of the objects were removed from analysis to avoid possible erroneous conclusions (see Sik et al . 2003). For the statistics, this resulted in the following number of animals per group: (1) for ITI 2 h, we used data of 10 SERT+/+ (two rats were eliminated), 10 SERT+/ – (two rats were eliminated) and 9 SERT−/ – rats (three rats were eliminated); (2) for ITI 4 h, we used data of 10 SERT+/+ (two rats were eliminated), 10 SERT+/ – (two rats were eliminated) and 11 SERT−/ – rats (one rat was eliminated); (3) for ITI 2 h, we used data of 10 SERT+/+ (two rats were eliminated), 9 SERT+/ – (three rats were eliminated) and 8 SERT−/ – rats (four rats were eliminated).

Statistical analysis Because there were several missing values, a split-plot analysis of variance (ANOVA) (genotype between subjects; ITI within subjects) would lead to loss of power because of list-wise deletion of missing cases. Therefore, we used a mixed regression model to analyze the data. Unlike ANOVA, the mixed regression model does not require complete data at all levels of the within-subjects factor, leading to a more efficient estimation of model parameters (Verbeke & Molenberghs 2000). We performed the mixed effects regression analysis using the Mixed Models procedure of the Statistical Package for Social Sciences for Windows version 15.0.0 (SPSS, Chicago, IL, USA).

Results First, we checked possible genotype differences in total exploration time during trial 1 and trial 2. Using a mixed effects regression model with heterogeneous compound symmetry covariance structure, a significant genotype by ITI interaction effect on the total exploration time in trial 1 was found (F4,59.586 = 2.666. P = 0.041). This interaction was caused by the fact that the SERT+/ – rats explored somewhat less in the ITI 4 condition, relative to their exploration times in ITI 2 and ITI 8. The SERT+/+ and SERT+/ – rats took relatively more time in exploring in the ITI 4 condition, relative to their exploration times in ITI 2 and ITI 8. For the total exploration time in trial 2, no significant main effect for genotype (F2,30.107 = 1.002. P = 0.379) or interaction effect (F4,53.828 = 1.754. P = 0.152) was found. To control for possible confounding, we decided to include total exploration time in trial 1 as covariate in our main analysis. For our main analysis, object recognition memory was measured after the three different ITIs (2, 4 and 8 h). An overview of discrimination index scores (d2), as actually observed in the three ITI conditions, is presented in Fig. 1. Genes, Brain and Behavior (2009) 8: 829–834

SERT deficiency impairs object memory

Figure 1: Effects of SERT deficiency on discrimination index d 2 in the object recognition test with different ITIs. ∗ P < 0.05 different from SERT+/ – and SERT−/ – rats.

Using the mixed effects regression model, the most parsimonious covariance structure for the model containing main and interaction effects for genotype and ITI, and containing exploration in trial 1 as covariate, was identified as heterogeneous compound symmetry. The estimated variances for the three ITI conditions ITI 2, ITI 4 and ITI 8 were 0.10, 0.12 and 0.16, respectively. The correlation between scores in different ITI conditions was estimated as 0.07. Using this model, exploration time in trial 1 had no significant effect on d2 (F1,66.910 = 1.751, P = 0.190). We therefore removed trial 1 from the model and subsequently analyzed the model with main and interaction effects involving genotype and ITI. The genotype by ITI interaction effect was found to be significant (F4,46.188 = 2.826, P = 0.035). The significant interaction effect between Genotype and ITI is the result of two conspicuous differences. First, in the ITI 2 condition SERT−/ – rats do not differ in object recognition from SERT+/+ rats (mean difference–0.005), but in the ITI 8 condition SERT−/ – rats score much lower than SERT+/+ rats (mean difference–0.622). This specific interaction effect was shown to be significant (t38.411 = −2.657, P = 0.011). Likewise, in the ITI 2 condition SERT+/ – rats do not differ in object recognition from SERT+/+ rats (mean difference 0.051), but in the ITI 8 condition SERT+/ – rats score much lower than SERT+/+ rats (mean difference–0.442). This specific interaction effect was also shown to be significant (t38.371 = −2.187, P = 0.035). The analysis model did not show any other significant effects.

Discussion The aim of the present study was to assess object memory in rats with different SERT genotypes following different ITIs. In a previous study, SERT+/+ , SERT+/ – and SERT−/ – rats showed normal object memory after a 1-h ITI (Olivier et al . 2008b). In the present study, it was found that SERT+/+ , SERT+/ – and SERT−/ – rats also show normal object memory with ITIs of 2 and 4 h. However, with an interval of 8 h between the trials of the object recognition test, only SERT+/+ rats showed object recognition, whereas a clear Genes, Brain and Behavior (2009) 8: 829–834

memory impairment was found in SERT+/ – and SERT−/ – rats. Apparently SERT+/ – and SERT−/ – rats show enhanced memory loss of object memory compared with SERT+/+ rats. These results indicate that optimal SERT functioning is important for object memory, especially with longer ITIs, and that disturbed serotonin homeostasis may influence this process. Lowering the serotonin levels in the brain with ATD is known to impair object memory in rats (Jans et al . 2007; Lieben et al . 2004a; Rutten et al . 2007). The frontal cortex and hippocampus are, among others, brain areas involved in cognition and memory (Dalley et al . 2004; Heidbreder & Groenewegen 2003; Squire & Zola-Morgan 1991; Wurtman et al . 1980). Previous research in the SERT−/ – rat has shown that basal intracellular/tissue serotonin levels in the frontal cortex and hippocampus are lower in SERT−/ – rats compared with SERT+/ – and SERT+/+ rats (Homberg et al . 2007a,b; Olivier et al . 2008b). Therefore, the results of the present study are in concordance with the repeatedly reported finding of impaired object memory in rats exposed to ATD. In humans, impaired long-term memory performance after ATD has also been frequently shown (Riedel et al . 2002; Schmitt et al . 2006). Although previous studies have shown that intracellular brain serotonin levels of SERT+/ – rats are comparable with serotonin levels in SERT+/+ rats (Homberg et al . 2007a,b; Olivier et al . 2008b), we found that SERT+/ – rats showed impaired object memory with the longest ITI, similar to SERT−/ – rats. This finding, together with the finding that SERT−/ – rats have still intact object memory with ITIs of 2 and 4 h, indicates that serotonin levels alone cannot fully explain the genotype differences in object memory with increasing ITI. Previous results have shown that serotonin brain tissue levels in frontal cortex and hippocampus in the SERT−/ – rat are comparable with those of SERT+/+ rats after ATD; and those levels are associated with impaired object memory (Olivier et al . 2008b). The absence of impaired object memory with an ITI of 2 and 4 h may indicate that adaptations have taken place in these rats to compensate the life-long low intracellular serotonin levels. It is likely that pre and postsynaptic serotonin receptors and perhaps other systems have adapted to the low serotonin levels. We previously showed that the sensitivity of the serotonin 1A receptors (5-HT1A ) is changed (Homberg et al . 2008; Olivier et al . 2008a). The 5-HT1A receptor is among others involved in learning and memory processes. Deficits in the performance of memory tasks produced by 5-HT1A receptor agonists seem to be related to the stimulation of the postsynaptic 5-HT1A receptors (Carli et al . 1992; Carli & Samanin 1992; Cole et al . 1994; Otano et al . 1999; Riekkinen 1994), whereas activation of the presynaptic 5-HT1A receptors leads to memory facilitation (Carli et al . 1998; Cole et al . 1994; Meneses & Hong 1994). This indicates an important role for the 5HT1A receptor on memory. Indeed, 8-OH-DPAT, a 5-HT1A receptor agonist, dose-dependently impaired the recognition memory in rats (Pitsikas et al . 2005). All together, these results suggest that changes in the sensitivity of 5-HT1A receptors (either pre or postsynaptically) in SERT+/ – and


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SERT−/ – rats may contribute to the impairment of delayed object memory. With respect to human SERT genotype, effects of ATD on cognition have been reported to differ between the s and l groups. In healthy volunteers, the s genotype group showed impaired verbal recall following tryptophan depletion, whereas the l genotype group showed no difference in recall between tryptophan depletion and controls. There were no genotype differences in recognition. Interestingly, regardless of treatment, the s genotype group has better overall accuracy in a pattern recognition memory task than the l group (Roiser et al . 2007), which measures recall after a 20-min delay. Opposite results were found in the present study but only after longer ITIs, where untreated SERT+/ – and SERT−/ – rats showed impaired object memory compared with SERT+/+ rats. Evidence for SERT modulation of delayed memory is limited. A study in healthy elderly subjects found a gene-dose-dependent effect of SERT on delayed recall on a verbal learning task, with lower scores in s-allele carriers (O’Hara et al . 2007). Payton et al . (2005), however, did not find an effect of SERT on cognition, including delayed memory. Functional variants in the l allele, lA and lG , do exist (Hu et al . 2006). The lG and s alleles have comparable levels of SERT expression, and both are lower than that of the lA allele. This may have influenced the outcome of several human studies that did not screen for these genotypes, and may have caused inconclusive results. In conclusion, SERT affects object memory in rats, like it affects memory in humans, indicating an important modulatory role of the serotonergic system in object memory. However, it appears that differences in brain serotonin levels cannot fully explain the SERT genotype effect on object memory in rats, and more research is needed to elucidate the exact role of SERT in object memory. We previously showed that SERT−/ – rats show depression-like symptoms (Olivier et al . 2008c), like the 5-HTTLPR-s allele increases risk to develop depression (Caspi et al . 2003). Given that depression is associated with memory impairments (Clark et al . 2009), our findings may contribute to further understanding of mechanisms underlying cognitive deficits in depression. That is, combining the findings object memory is hippocampus dependent (Bachevalier & Meunier 1996; Mumby et al . 1996; Squire 1992; Squire & Zola 1996) and that the 5-HTTLPR s allele is associated with neurodevelopmental structural changes in the hippocampus (O’Hara et al . 2007) leads to the suggestion that constitutive lower SERT function predisposes to both depressive mood and memory impairments because of common neurodevelopmental changes in, for instance, the hippocampus.

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Acknowledgments We thank Edwin Cuppen for his co-operation and Mark Verheul for genotyping of the rats.

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