PS1 mice

European Journal of Pharmacology 701 (2013) 152–158

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Behavioral pharmacology

The effects of subchronic D-serine on left–right discrimination learning, social interaction, and exploratory activity in APPswe/PS1 mice Mohammed Filali a,n, Robert Lalonde b a b

Neurobehavioral Phenotyping Platform, Neuroscience Group, CHUQ Research Center, Department of Molecular Medicine, Laval University, Que´bec, Canada University of Rouen, Faculty of Sciences, Department of Psychology, ICONES Laboratory, 76821 Mont-Saint-Aignan, France

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 September 2012 Received in revised form 12 December 2012 Accepted 19 December 2012 Available online 28 December 2012

Glutamatergic neurotransmission is crucially involved in memory and cognition and severely affected patients with Alzheimer’s disease. Modulation of NMDA receptors with agonists may reverse their late-stage symptoms. The effects of subchronic treatment of the NMDA receptor agonist, D-serine, were evaluated in APPswe/PS1 mutant mice harboring Ab plaques in brain, regarding spatial discrimination learning, open-field activity, and social interaction in a three-chambered apparatus. D-serine (50 mg/kg, i.p.) was superior to placebo in mutant mice during the reversal phase of left–right discrimination learning without affecting acquisition. The drug caused weaker effects in counteracting open-field hyperactivity and low social interaction with an unfamiliar stimulus mouse. These results indicate a favorable action of an NMDA receptor agonist on reversal learning in transgenic mice with amyloid pathology. & 2012 Elsevier B.V. All rights reserved.

Keywords: Alzheimer’s disease D-serine APPswe/PS1 mice Left–right discrimination learning Reversal learning Perseverative tendency Social behavior Open-field

1. Introduction D-serine is synthesized from the non-essential amino acid L-serine in a reaction catalyzed by serine racemase (Wolosker et al., 1999). Both D-serine and serine racemase are found in neurons and astrocytes (Kartvelishvily et al., 2006; Miya et al., 2008; Schell et al., 1995, Schell, 2004; Yoshikawa et al., 2007; Williams et al., 2006), though the enzyme is mostly found in neurons (Kartvelishvily et al., 2006; Miya et al., 2008; Yoshikawa et al., 2007) and the substrate mostly in astrocytes and shuttling betwen the two cell types (Wolosker, 2011). Serine racemase can also help convert either L-serine or D-serine to pyruvate (De Miranda et al., 2002; Foltyn et al., 2005, Scolari and Acosta, 2007; Strı´sovsky´ et al., 2003). The main function of D-serine is to act as a co-agonist at (n-methyl-D-asparte) NMDA receptors (Fadda et al., 1988; Hashimoto et al., 1993), essential for long-term potentiation (LTP) (Fossat et al., 2012; Henneberger et al., 2010; Yang et al., 2003). Mice with a null mutation for Srr, encoding serine racemase, were less vulnerable to NMDA-induced damage (Inoue et al., 2008). Moreover, D-serine can prevent object recognition

n

Corresponding author. Tel.: þ418 654 2296; fax: þ418 654 2761. E-mail addresses: [email protected], mfi[email protected] (M. Filali). 0014-2999/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2012.12.018

memory deficits caused by NMDA receptor antagonists (Bado et al., 2011; Hashimoto et al., 2008; Karasawa et al., 2008). For these reasons, D-serine has been discussed as a treatment option in schizophrenia and Alzheimer’s disease (Butterfield and Pocernich, 2003; Fuchs et al., 2011; Scolari and Acosta, 2007). In Alzheimer’s disease, a two-stage process has been proposed with respect to glutamatergic transmission, neuronal death mediated by hyperactive NMDA receptors followed by destruction of glutamatergic-containing neurons (Olney et al., 1997). There is some available evidence of such cell-death mediated processes (Butterfield and Pocernich, 2003) and NMDA receptors eventually decline in Alzheimer brain (Greenamyre, 1986; Sze et al., 2001). We previously evaluated the effects of an NMDA receptor antagonist, memantine, and found improved reversal learning of left–right discrimination in APPswe/PS1 bigenic mice (Filali et al., 2011a) expressing APP with the Swedish mutation and PS1 with the A246E mutation (Borchelt et al., 1997), causing age-related increases in soluble and insoluble Ab42 and Ab40 and plaque formation (Marutle et al., 2002, Wang et al., 2003) and the impairment of the reversal phase of left–right discrimination learning (Filali et al., 2009), a prefrontal cortex-mediated function (Kolb, 1984), as well as place learning in the Morris maze (Liu ¨ et al., 2002). The susceptibility of reversal et al., 2002; Puolivali training to amyloid processes is further indicated by the finding of improved performance in transgenic mice expressing MMP9,

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which favors the non-amyloid forming a-secretase pathway (Fragkouli et al., 2012). In the present report, the effects of subchronic D-serine injections were examined in the same bigenic. Some reports indicate that this drug may be useful in normal aging. D-serine concentrations have been found to be lower in the hippocampus of aged rats than young ones (Mothet et al., 2006; Potier et al., 2010). In addition, the drug prevented age-related reductions in NMDA receptor synaptic potentials and LTP in rats (Mothet et al., 2006; Potier et al., 2010; Turpin et al., 2011) as well as LTP of the senescence-accelated mouse strain, SAM-prone/8 (Yang et al., 2005) and also long-term depression (LTD) in young adult rats, together with memory retrieval in the Morris water maze (Zhang et al., 2008). In view of these results in normal aging, our hypothesis is that D-serine may counteract pathological aging as reflected in a middle-aged mutant with amyloid deposition. The mice were also evaluated in open-field activity and social interaction in a three-compartment apparatus to gauge whether the drug has a similar impact on exploratory activity. A single 50 mg/kg dose was used. Although facilitation of memory has been reported at doses as high as 800 mg/kg (Shimazaki et al., 2010), preliminary experiments indicated that lower doses may affect the present testing procedures.

2. Materials and methods 2.1. Transgenic animals Transgenic mice bearing a chimeric human/mouse APP gene with the Swedish mutation combined with the A246E variant of the human PS1 gene, B6C3-Tg(APP695)3Dbo Tg(PSEN1)5Dbo/J (strain number: 005864), were bred in our facility from those purchased from the Jackson Laboratory (Bar Harbor, ME, USA). The mice were first generated on a B6C3 background, then backcrossed for at least 10 generations to C57BL/6J. Male transgenics were bred with female wild-type, yielding approximately 25% transgenics. Group-housed male APPswe/PS1 transgenic and littermate wild-type mice (N¼56, 9–12 month-old) were separated into 4 groups: APPþsaline 0.9%, n¼13; APPþD-serine 50 mg/kg, n¼13; wild-typeþsaline 0.9%, n¼15 and wild-typeþD-serine 50 mg/kg, n¼15. D-serine was purchased from Sigma-Aldrich (St-Louis, MO, USA) and injected i.p. 30 min before behavioral testing in a volume of 5 cc/kg and for 3 weeks prior to the experiment. All mice had continuous access to food and water in a temperature-controlled room under natural lighting conditions with a 12/12 h light–dark cycle (lights on at 7:00) and their health status regularly checked with a modified version of the SHIRPA primary screen (Rogers et al. 1997). The genotype status of all newborn pups was confirmed by DNA analysis of tail biopsies. Animals were tested during the light phase (range: 9:00–16:00) by an experimenter blind to genotype and following guidelines of the Canadian Council on Animal Care, in a protocol approved by the Animal Welfare Committee at Laval University. 2.2. Behavioral assessments The open-field test was given first, followed by the 3-chamber social test and left–right discrimination learning, with no intervening day of rest between each testing day. The experiments were conducted in two series of mice (N ¼28) under identical conditions. 2.2.1. Open-field The circular open-field was made of clear plexiglas (diameter: 76 cm, height: 40 cm) equipped with a video-tracking system

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(Any maze, Stoelting Co, Wood Dale, IL, USA). Each mouse was placed in the middle of the open-field for a single 5-min session with the experimenter out of its view. Distance traveled was recorded. After each trial, fecal boli were removed and the floor was wiped clean with a damp cloth and dried.

2.2.2. Social interaction Social behaviors were evaluated in a three-compartment apparatus made of clear plexiglas (length: 69 cm, width: 13 cm, height: 15 cm), each separated by side-doors (8 cm  8 cm). The two lateral compartments contained a small circular plexiglass cage (diameter: 9 cm, height: 15 cm) with numerous mesh-like holes (diameter: 1.2 cm) yielding olfactory cues. Mouse activity was recorded for 15 min with a videocamera and analyzed with the same video-tracking system as for open-field activity. Each mouse was placed inside the central compartment and explored the entire apparatus for a 5-min habituation period, the doors on either side being open and all three compartments being empty (min 1 to 5). In the sociability test, an unfamiliar male mouse (stranger) of the same background strain and age was introduced inside either lateral compartment for 5 min, while the other contained an identical empty cage (min 6 to 10). The tested mouse was then returned in the central compartment and explored any of the three compartments for 5 min (min 11 to 15). Measures included number of entries in the compartment that had contained the stranger and the one containing the empty cage on the opposite side, time spent in the immediate vicinity (5 cm) of the cage that had contained the stranger and the one containing the empty cage and % time in vicinity calculated thus: time spent in the cage that had contained the stranger minus time spent in the empty cage divided by total time spent with either cage that had contained the stranger or empty cage.

2.2.3. Left–right discrimination learning The T-maze (length of stem 64 cm, length of arms 30 cm, width 12 cm, height of walls 16 cm) was made of clear plexiglass and filled with water (2371 1C) at a height of 12 cm. A platform (11  11 cm2) was submerged at the end of the target arm 1 cm below the surface. During the first two trials, platforms were placed on both arms to test turning preferences. Afterwards, only the least chosen arm, if any, was reinforced, with approximately the same number of mice being reinforced on either side. APPswe/PS1 and control mice were placed in the stem of the T maze and swam either to the left or the right until finding the submerged platform up to a maximum of 60 s. If the animals did not find the platform within this time limit, they were gently guided to it. After reaching the platform, the mice remained on it for 20 s and then placed back in the maze for up to a maximum of 48 trials, except for a 10-min rest period after each 10-trial block. A mouse was considered to have achieved criterion after 5 consecutive errorless trials. The reversal learning phase was then conducted 2 days later, when the same protocol was repeated except that the mice were trained to find the escape platform on the opposite side. Escape latencies, trials before criterion, and swimming paths were recorded. Based on their trajectory pattern on trial 12, the animals were subdivided in 3 types of strategy (S1: direct, S2: intermediary, S3: complex with perseveration and return to the same area). 2.3. Statistical analyses For parametric data, intergroup differences were evaluated by ANOVA followed by unpaired t-tests and for non-parametric data by Mann–Whitney U and Wilcoxon tests. To compare strategies seen in the T-maze, the two-sided w2 test was used. All comparisons were done with Prism 5 software (GraphPad Software,

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San Diego, CA). The data are expressed as mean values 7S.E.M. with P values less than 0.05 considered significant.

3. Results 3.1. Open-field In the open-field (Fig. 1A), saline-injected APPswe/PS1 mutants were more active than saline-injected wild-type (U¼ 43, P o0.05, Mann–Whitney U test, Fig. 1B). However, D-serine eliminated this difference, as drugged mutants and non-mutants no longer differed (P40.05, Fig.1B). The D-serine injected APP mice were not different from saline-injected APP mice and the Dserine injected wild-type mice were not different from salineinjected wild-type. Comparison between first and final minutes of the test revealed a decline in motor activity in the wild-type/ saline group (W¼92, Po0.01, Wilcoxon signed-rank test), a sign of intrasession habituation (Fig.1C et 1D). The same result was found with wild-type/serine (W¼82, P o0.05) and APP/serine (W¼69, Po0.05) groups, but the APP/saline one was at borderline significance (W¼55, P¼0.0574). 3.2. Social interaction Saline-injected mutants differed from saline-injected wild-type in % time spent in the vicinity of the cage that had contained the stimulus mouse (U¼49, Po0.05, Fig. 2B3). Unlike wild-type, mutants preferred to explore for a relatively longer time the vicinity of the empty chamber than the one that had contained the stimulus mouse.

On the contrary, the groups did not differ in absolute time spent in the vicinity of the stimulus mouse (Fig. 2B2) or in entries inside the compartment that had contained the stranger or the one containing the empty cage (Fig. 2B1). As in the previous test, D-serine eliminated this difference, because mutants and non-mutants no longer differed (P40.05, Fig. 2B3). The D-serine injected APP mice were not different from saline-injected APP mice and the D-serine injected wild-type mice were not different from saline-injected wild-type. All groups explored equally the empty chambers in the initial period (data not shown, P40.05). 3.3. Left–right discrimination learning D-serine had no effect on acquisition of left–right discrimination learning of APPswe/PS1 or wild-type mice (Fig. 3A). But during reversal training, analysis of trials to criterion revealed a main effect for mouse group (F1,52 ¼21.82, Po0.001) and drug (F1,52 ¼10.01, Po0.01) as well as their interaction (F1,52 ¼4.37, Po0.05). Saline-treated mutants performed worse than salinetreated wild-type (t26 ¼4.2, Po0.001) and D-serine once again eliminated this difference (P40.05). There was no difference between D-serine and placebo for non-mutants, but there was a difference between D-serine and placebo for mutants (t24 ¼ 2.9, Po0.01). Analysis of escape latencies during the reversal phase revealed significant effects for mouse group (F1,52 ¼ 9.92, Po0.01) and drug (F1,52 ¼4.36, Po0.05), but not their interaction (F1,52 ¼0.27, P40.05). When animals were classified according to strategy of navigational paths on trial 12, the number of animals exhibiting an S3-type strategy was lower in the APP/serine group than in the APP/saline group (w2 test, Po0.05; Fig. 3B).

Distance traveled (m)

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Fig. 1. Automated open-field (A). Activity levels (B–D). y p o0.05 wild-type vs APPswe/PS1 (Mann–Whitney U test); nPo 0.05 and nnPo 0.01 for comparisons between first minute vs last minute (Wilcoxon signed-rank test).

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B1

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pt y

ra ng

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Percentage change for time vicinity (Emty vs. stranger) in seconds

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Fig. 2. (A) Experimental design. (B) Social interaction. B1—Number of entries inside each chamber, B2—time spent in the immediate vicinity of the empty cage or stimulus mouse cage. B3—relative change in time spent in immediate vicinity of the stimulus mouse vs time spent in the vicinity of empty cage. nPo 0.05, wild-type vs APPswe/PS1 (Mann–Whitney U test).

4. Discussion In contrast to the lack of any effect during acquisition of left– right discrimination learning in a T-maze, systemic D-serine caused fewer errors and lower escape latencies than salineinjected APPswe/PS1 bigenics during the reversal phase. In an analogous fashion, D-serine injected i.p. before the probe trial facilitated memory retrieval of young adult rats in the Morris water maze (Zhang et al., 2008). Moreover, peripherally injected D-cycloserine, a serine analog, facilitated acquisition of the hidden platform subtask of the Morris water maze in young (Lelong et al., 2001) and aged (Baxter et al., 1994) rats. However, as found in T-maze acquisition, D-serine injected i.p. did not affect a matching-to-place task in rats swimming in a water maze (Stouffer et al., 2004). Although general results favor the hypothesis of D-serine-induced facilitation of spatial learning or its reversal in normal and pathological aging, the effects appear to

be task-specific. The improvement may be due to facilitation of NMDA receptor-mediated transmission, as indicated by the facilitation of LTP caused by this drug (Mothet et al., 2006; Potier et al., 2010; Turpin et al., 2011). These experimental findings are in accordance with some clinical data. In a double-blind study, patients with probable Alzheimer’s disease receiving oral D-cycloserine administration twice daily for 10 weeks had better implicit memory of perceptually degraded words than those receiving placebo (Schwartz et al., 1996). Repeated oral D-cycloserine administration to such patients also improved the cognitive part of the Alzheimer’s Disease Assessment Scale relative to placebo (Tsai et al., 1998). Moreover, milacemide, a glycine prodrug acting at NMDA receptors (Herting, 1991), facilitated verbal learning of aged nondemented adults and also young adults (Schwartz et al., 1991). The favorable impact of D-serine administration in APPswe/ PS1 mutants extended more weakly to motor activity. Indeed,

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D-Serine

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60 % of animals

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Fig. 3. T-water maze left–right discrimination learning and reversal. Mean 7S.E.M. escape latencies (A1 and A3) and trials to criterion (A2 and A4) during acquisition and reversal. APP/saline vs. wild-type/saline nPo 0.05, unpaired t-test. (B1) Representative swim paths during the reversal phase in the T-maze. (B2) Percentage of animals using the S3 swim path strategy as a function of treatment. nAPP/saline vs. wild-type/saline, Po 0.05; two-sided w2 test.

placebo-injected APPswe/PS1 mice were more active in the openfield than placebo-injected wild-type, the bigenic being susceptible to this pattern (Filali et al., 2011b), but D-serine canceled this intergroup difference, though D-serine-injected mice did not differ from placebo in either mouse group. While D-serine blocked dizocilpine-induced hyperactivity in normal mice (Nilsson et al., 1997), it remains to be determined whether hyperactivity in the bigenic is due to impaired transmission at the NMDA receptor, the latter being a characteristic of the later stage of patients with Alzheimer dementia (Greenamyre, 1986; Sze et al., 2001). In addition to reversal learning and ambulatory activity, D-serine seemed to exert some impact on social interaction towards an unfamilar mouse from the same background strain inside the three-chamber set-up. Unlike saline-injected wild-type, saline-injected APPswe/PS1 mutants interacted for a relatively longer time with the empty cage than the one where the stimulus mouse was previously placed, but D-serine eliminated this group difference. Likewise, D-serine increased social interaction inside the three-chamber apparatus in two normal mouse strains differing in willingness to explore an unfamilar stimulus mouse: Balb/c, timid in this regard, as well as the bolder Swiss-Webster strain (Deutsch et al., 2011). D-serine and its analog, D-cycloserine, enhanced social exploration in Balb/c mice exposed to two other conditions, increasing the amount of time spent in a compartment containing the stimulus mouse and the amount of time sniffing an inverted cup containing the stimulus mouse (Jacome et al., 2011a,b). Moreover, D-serine injected in rats after a social encounter facilitated memory of an unfamiliar rat placed inside the same cage (Shimazaki et al., 2010). These experimental data should encourage clinical testing of NMDA receptor agonists on neuropsychiatric symptoms of Alzheimer patients marked by poor caregiver compliance (Cummings et al., 2008). The relation between D-serine levels and dementia has been explored. In particular, D-serine levels in ventricular cerebrospinal fluid increased in patients with Alzheimer’s disease, indicating reduced levels in the brain (Fisher et al., 1998). The increase in

serine racemase mRNA in the hippocampus of these patients may be a compensatory response to the reduced levels (Wu et al., 2004). In addition, the ratio of D-serine to the total serine pool decreased in the serum of these patients, reflecting a deficient state (Hashimoto et al., 2004). On the contrary, no change in D-serine levels was reported in post-mortem brain samples of these patients (Chouinard et al., 1993; Nagata et al., 1995). It remains to be determined what is the status of the amino acid in murine Alzheimer-like mutants. The favorable impact of D-serine on reversal training and to a lesser extent on social interaction and hyperactivity may encourage use of this substance in further clinical trials of Alzheimer’s disease, presumed to be a two-stage process with respect to glutamatergic transmission, the final one being mediated by hypoactive NMDA receptors caused by destruction of glutamatergic-containing neurons (Olney et al., 1997). Medications of especially use should include those with benefits on memory as well as neurosychiatric symptoms such as agitation and poor compliance. Despite its potentially favorable actions, D-serine must be considered as a potential promoter of cell death (Scolari and Acosta, 2007), especially in the early stage of Alzheimer’s disease, presumed to be characterized by glutamate-mediated cell death (Olney et al., 1997). In cultured microglial cells, Ab stimulated D-serine release, possibly to toxic levels (Wu et al., 2004). Mice with a null mutation for Srr, encoding serine racemase, characterized by lower than normal brain D-serine levels, were less vulnerable to Ab-provoked damage when injected in the hippocampus (Inoue et al., 2008). There is a link between glial cells and neuronal damage (Aschner et al., 1999) and glutamate excitotoxicity is involved in other conditions such as ischemia and reperfusion (Swanson et al., 2004). Thus, according to the two-stage model of Alzheimer’s disease (Olney et al., 1997), D-serine may slow down the disease process in the late hypoactive glutamatergic stage but become harmful in the early hyperactive stage. These aspects may be further evaluated in different mutants at different age levels.

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Acknowledgments This work was supported by a grant of the Canadian Institutes of Health Research (CIHR) to Serge Rivest.

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