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Human Molecular Genetics Advance Access originally published online on May 20, 2007
Human Molecular Genetics 2007 16(14):1708-1719; doi:10.1093/hmg/ddm119
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impairments in impulse control in mice transgenic for the human FTDP-17 tauV337M mutation are exacerbated by age

Sarah L. Lambourne1, Trevor Humby1,3,4, Anthony R. Isles1,3,4, Piers C. Emson2, Maria G. Spillantini5 and Lawrence S. Wilkinson1,3,4,*

1 Laboratory of Cognitive and Behavioural Neuroscience and 2 Laboratory of Molecular Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK, 3 Behavioral Genetics Group, Cardiff University, Cardiff, UK, 4 Department of Psychological Medicine, School of Psychology, Cardiff CF14 4XN, UK and 5 Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, UK

* To whom correspondence should be addressed. Tel: +44 2920870357/2920747942; Fax: +44 2920874858; Email: wilkinsonl{at}cardiff.ac.uk

Received February 23, 2007; Accepted April 27, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Abnormalities in microtubule-associated tau protein are a key neuropathological feature of both Alzheimer's disease and many frontotemporal dementias (FTDs), including hereditary FTD with Parkinsonism linked to chromosome 17 (FTDP-17). In these disorders, tau becomes aberrantly phosphorylated, leading to the development of filamentous neurofibrillary tangles in the brain. Here we report, in a longitudinal ageing study, the sensorimotor and cognitive assessment of transgenic mice expressing the human tauV337M (‘Seattle Family A’) FTDP-17 mutation, which we have previously shown to demonstrate abnormalities in brain tau phosphorylation. The data indicated highly specific effects of transgene expression on the ability to withhold responding in a murine version of the 5-choice serial reaction time task, behaviour consistent with deficits in impulse control. Ageing exacerbated these effects. In young tauV337M mice, increased impulsivity was present under task conditions making inhibition of premature responding more difficult (longer inter-trial intervals) but not under baseline conditions. However, when older, the tauV337M mice showed further increases in premature responding, including under baseline conditions. These impulse control deficits were fully dissociable from sensorimotor or motivation effects on performance. The findings recapitulate core abnormalities in impulsive responding observed in both frontal variant FTD and FTDP-17 linked to the tauV337M mutation in humans.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Abnormalities in the microtubule-associated tau protein are a key neuropathological feature of several brain disorders, including Alzheimer's disease (both sporadic and familial), progressive supranuclear palsy, frontotemporal dementias (FTDs) and FTD with Parkinsonism linked to chromosome 17 (FTDP-17). In such disorders, tau becomes aberrantly phosphorylated, leading to the development of aggregates of paired helical filaments (PHFs) and/or straight filaments of tau within the brain (reviewed in 1). The discovery of coding region and intronic mutations in the tau gene in FTDP-17 has indicated the connection between tau dysfunction, neurodegeneration and dementia and has motivated the development of genetic animal models focusing on tau manipulations. The production of transgenic mice expressing FTDP-17 tau mutations, which demonstrate filamentous neuropathology similar to that seen in human tauopathy conditions, has previously been described [e.g. G272V (2), P301L (3,4), P301S (5), V337M (6,7), R406W (8)]. However, although these data suggest relevance of the transgenic models to human tauopathy at the molecular and biochemical levels, limited investigation of the effects of transgene expression on the cognitive and behavioural abilities of the mice has been undertaken, an issue of some importance given that the primary symptoms associated with FTDP-17 are deficits in cognitive and behavioural functioning. One reason for the relative lack of behavioural data may be that previous mouse models expressing the P301L and P301S tau mutations can, in some cases, develop severe motor disturbances from as early as 4.5 months (4,5). It is likely that such gross motor effects would confound many of the behavioural tasks that could be potentially undertaken in these mice.

In the work described here, we used mice expressing the FTDP-17 V337M (valine to methionine) mutation (9) in a human tau transgene. The form of dementia linked to the tauV337M mutation, which was originally identified in an American family of Czechoslovakian descent (‘Seattle Family A’), is characterized neuropathologically by tau neurofibrillary tangles (NFTs) in the frontal and parietal cortex, temporal lobe and amygdala and clinically by symptoms of personality change, anti-social behaviour, risk-taking and paranoid ideation, followed by deficits in attention, confusion and memory loss (10). The clinical symptoms of the tauV337M mutation bear strong similarity to that seen in frontal variant FTD (fvFTD), in which patients present with profound changes in personality and social behaviour, inattention, dis-inhibition, impulsiveness and stereotypic ritualistic behaviours (11–14). Using a longitudinal design, we tested the tauV337M mice (15) in a murine version of the 5-choice serial reaction time task (5-CSRTT) developed previously in our group to assess the aspects of attention and impulse control (16,17). In contrast to several other FTDP-17 mouse models, there was no evidence of sensorimotor disturbance in tauV337M mice up to 24 months of age. The data did, however, reveal large effects of transgene expression on impulsive responding in the 5-CSRTT that were exacerbated by age. These findings recapitulate, for the first time in a transgenic mouse model, behavioural abnormalities seen in clinical cases of both fvFTD and FTDP-17 linked to the tauV337M mutation in humans.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Expression of the human tauv337m transgene in mouse brain
Expression of the tauV337M transgene was under the control of the brain-specific modified mouse Thy-1 promoter (15). In situ hybridization data obtained in sagittal brain sections from mice aged 6 months (Fig. 1A) indicated high levels of expression of human tau mRNA in the cerebral cortex, hippocampus and pons, with very little expression identified in the striatum or cerebellum. No effects of transgene expression on endogenous mouse tau transcripts were identified (Fig. 1B). Immunohistochemical analysis in 6-month-old mice using the phosphorylation-independent human-specific T14 tau antibody revealed that the spatial distribution of human tau protein largely followed the pattern of human tau mRNA expression, with neurons stained in the frontal cortex, hippocampus and pons, and little staining present in the striatum. No staining was identified in littermate wild-type mice (Fig. 1C). Further description of the molecular and biochemical features of the tauV337M mouse model can be found in a previous study (15).


Figure 1
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  		Figure 1. Spatial distribution of tauV337M mRNA and protein. Sagittal brain sections (12 µm) from wild-type (WT) and tauV337M (Tau) mice were analysed by in situ hybridization using radiolabelled probes specific to human tau (A) and mouse tau (B) mRNA. Free-floating sagittal sections [30 mm, from 6-month-old tauV337M (a–e) and littermate wild-type mice (f)] were immunohistochemically stained using the human-specific anti-tau T14 antibody. A section from the frontal cortex [wild-type littermate (f)] is representative of the level of staining throughout wild-type littermate brains (C). Scale bar = 100 mm. The data are representative of four independent samples per group.

 
Absence of motor deficits in the tauv337m mice: relationship with brain and spinal cord tauopathy
As noted in the introduction, much previous work using transgenic mice expressing FTDP-17 mutations, including a study involving mice expressing the tau P301S mutation (5), has shown an association between transgene expression and profound motor disturbances, leading to hindlimb paralysis, with symptoms emerging from as early as 4.5 months of age. No such motor effects were observed in the tauV337M mice in two separate tests of motor function. General locomotor activity (LMA) data are shown in Figure 2A. There were no significant effects of either GENOTYPE (F1,28 = 0.13, n.s.) or AGE (F1,28 = 2.16, n.s.) on the total number of infrared beam breaks recorded during a 2 h period. Furthermore, when the pattern of activity was examined in more detail over 24, 5 min bins, no group differences were present, with all groups exhibiting the expected gradual habituation to the novelty of the test chamber over the 2 h assessment period (data not shown). There were also no effects on the ability to maintain balance on the rotarod apparatus. Thus, although, in general, mice were quicker to fall from the rotarod at faster speeds (cf. Fig. 2B with C), the latency to fall from the rotarod at the highest speed was unaffected by either GENOTYPE (F1,28 = 0.12, n.s.) or AGE (F1,28 = 1.73, n.s.).


Figure 2
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  		Figure 2. Neuropathology of tauV337M mice. Mice were tested using LMA and rotarod apparatus to assess for motoric deficits (A–C). The LMA apparatus contains a transverse infrared beam at either end of a clear Perspex box. The total number of beam breaks performed by young (6 months) and old (24 months) wild-type (WT, black bars) and tauV337M (Tau, white bars) mice during a 2 h session was analysed. No significant differences relating to age or genotype were identified (A). On the rotarod, the latency to fall in a 60 s test was measured at increasing speeds of rotation. There were no significant age or genotype differences identified either at the low speed (24 r.p.m.) (B) or at the top speed (44 r.p.m.) (C). Data are the mean for each group (±SEM, n = 8). Free-floating sagittal sections (30 mm, 6-month-old mice) were immunohistochemically stained using the AT8 anti-phospho-S202/T205 tau antibody. Intracellular neuronal staining was identified in tauV337M mice, but not in littermate wild-type mice and was particularly localized in the regions shown (D). Bielschowsky silver staining revealed the presence of NFTs to be localized to the pons region of 12-month-old tauV337M mice. No staining was identified in the hippocampus of tauV337M mice, and no staining was seen in the brains of littermate wild-type mice (E). Scale bar = 100 mm. The data are representative of four independent samples per group. The presence of sarkosyl insoluble PHF tau was assessed in forebrain, hindbrain and spinal cord preparations from 24-month-old wild-type, tauV337M and tauP301S mice by western blotting, using the T14 antibody to human tau. PHF tau was identified in the forebrain of tauV337M mice, but not in wild-type. No specific bands were present in hindbrain or spinal cord preparations from wild-type or tauV337M mice. TauP301S mice exhibited strong bands of insoluble PHF tau in forebrain, hindbrain and spinal cord preparations (F).

 
We tested whether the absence of genotype effects on motor performance in the tauV337M mice was associated with underlying effects on indices of neuropathology by comparing the tauV337M mice with the tauP301S mouse model which do show motor deficits. Immunohistological analysis of brain sections from 6-month-old tauV337M mice stained with the AT8 phospho-specific anti-S202T205 tau antibody indicated widespread tau phosphorylation. Phosphorylated tau protein was identified in many of the brain regions where human tau was previously shown to be expressed, including the frontal cortex, hippocampus and regions of the mid- and hindbrain, including the medulla and pons (Fig. 2D). Bielschowsky silver staining in 12-month-old tauV337M mice was consistent with the presence of a small number of NFTs, which were found to be highly localized to the brainstem, in particular in the pons (Fig. 2E). No specific staining could be identified in hippocampal or cortical regions of the brain. Using western blotting methods, sarkosyl insoluble PHF tau was identified in the forebrain of 24-month-old tauV337M mice, but not in hindbrain or spinal cord preparations (Fig. 2F). For comparison, sarkosyl insoluble forebrain, hindbrain and spinal cord preparations from 5-month-old tauP301S mice [shown to exhibit PHF tau (5)] were also assessed. PHF tau was present at considerably higher levels in the forebrain of tauP301S mice than in tauV337M mice and was also found to be present at high levels in hindbrain and spinal cord (Fig. 2F), the latter of potential relevance to the motor deficits seen in the tauP301S mice (5).

Increased impulsive behaviour by tauv337m mice in the 5-CSRTT: only old tauv337m mice affected under baseline conditions
The 5-CSRTT tests the ability of subjects to make a correct response in response to a brief flash of light occurring in one of five locations. Briefly, in the murine version of the test (see Materials and Methods) (16,18,19), the task involves a succession of trials requiring the animal to orientate towards the response panel, to wait 5 s (under baseline conditions), and then make a response by nose poking where the light flash occurs. A correct response results in the delivery of reward, following which the next trial begins. The task contains many elements of the continuous performance tasks used to assess the aspects of attention and response control in humans (20). The 5-CSRRT task has been extensively characterized in humans (21–23), rats (17) and by our group in mice (16,18,19) and provides dissociable measures of attention (indexed by discriminative accuracy) and response control (indexed by premature responding, i.e. responding during the 5 s pause or ‘inter-trial interval (ITI)’ immediately before the presentation of the light stimuli). The task also provides a number of measures relating to motivation and speed of processing, which can be used to assess the specificity of any behavioural effects.

A reinforcer preference test, conducted prior to initial training in the 5-CSRTT, confirmed that both tauV337M and wild-type mice showed a similar preference for the condensed milk reinforcer (10% condensed milk) used to motivate performance in the task over water (mean percentage preference: tauV337M 70.3% ± 12, wild-type 72.8% ± 5.1–effect of GENOTYPE, F1,27 = 0.05, n.s; mean total volume drunk (ml): tauV337M 0.9 ± 0.1, wild-type 1.0 ± 0.1–effect of GENOTYPE, F1,27 = 0.56, n.s.). There were also no effects of genotype on behaviour during the basic shaping of the 5-CSRTT task, which involved habituation to the test chamber and learning the relationship between light onset in one of the five stimulus locations and the delivery of a food reward (data not shown). Similarly, during initial training towards the baseline stimulus duration of 0.8 s, genotype was without effect and all the younger animals showed the typical training profile of gradual reductions in reaction time (effect of GENOTYPE, F1,319 = 0.224, n.s; effect of TRAINING LEVEL, F10,319 = 120.3, P < 0.001) and increases in discriminative accuracy (effect of GENOTYPE, F1,319 = 0.5, n.s; effect of TRAINING LEVEL, F10,319 = 6.3, P < 0.001) as the stimulus durations were made progressively shorter, this pattern of behaviour being indicative of high levels of stimulus control (16,24). Re-acquisition of the task at 24 months of age revealed main effects of age and interactions between age and genotype. The mice, when older, showed the same pattern of training down to the baseline stimulus duration of 0.8 s but at stable baseline performance showed a general reduction in discriminative accuracy (Fig. 3A; effect of AGE, F1,42 = 16.96, P < 0.001), a general tendency to be slower when responding to the stimulus light (Fig. 3B; effect of AGE, F1,42 = 0.83, n.s) and a marked and specific increase in the number of premature responses made by the tauV337M mice as indicated by the significant interaction between GENOTYPE and AGE (Fig. 3C; F1,42 = 23.96, P < 0.001). The increase in premature responses made by the older tauV337M mice indicated a relative inability to withhold responding during the baseline 5 s ITI immediately prior to the stimulus onset. These effects, observed under baseline task conditions, were stable and enduring and were present throughout the entire testing period (Fig. 3C). Furthermore, the effects on impulsive responding were highly discrete and occurred in the absence of interactions between genotype and age across a wide range of potentially confounding factors (Table 1). Video evidence confirmed that genotype and age had no effects on the basic behavioural strategy utilized in the 5-CSRTT, whereby animals adopted a central position and scanned the stimulus array.


Figure 3
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  		Figure 3. Increased impulsive responding of old tauV337M mice at stable baseline performance in the 5-CSRTT Acquisition of the 5-CSRTT by wild-type (WT) and tauV337M (Tau) mice began at 4 months of age, with mice reaching stable baseline performance by approximately 7 months of age. The stimulus duration was gradually reduced from 32 s to the baseline of 0.8 s, using the performance criteria of two consecutive sessions with >80% accuracy (i.e. ratio of correct:total responses) and <20% omissions, correct reaction time less than the stimulus duration and >50 trials. Re-acquisition of the task began at 24 months of age, with an initial training stimulus duration of 4 s. At baseline, there were no effects of genotype on response accuracy (A) or correct reaction time (B) in either the young or old animals. However, the older tauV337M mice consistently performed an increased number of premature responses compared with the other groups (C). Data shown are the number of premature responses performed, taken from an average of two consecutive sessions, following a minimum of five sessions at stable baseline performance immediately prior to the first task manipulation and at the end of the testing regime (old late). Data are the mean for each group (±SEM; young wild-type n = 15, young tauV337M n = 15, old wild-type n = 7, old tauV337M n = 8).

 


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  		Table 1. General task measures in the 5-CSRTT

 
5-CSRTT task manipulations taxing inhibitory control revealed impulsive responding in young tauv337m mice and exacerbated impulsive behaviour in old tauv337m mice
Performance in the 5-CSRTT was probed using a number of task manipulations designed to tax dissociable elements of behaviour. Figure 4A illustrates the effects of increasing the ITI from 5 s (baseline) up to 8 s. As expected (since this increases the length of time, the subject must wait before reacting to the stimulus light), this manipulation increased premature responding across all groups (effect of TASK MANIPULATION, F3,196 = 26.55, P < 0.001). Increasing the ITI also uncovered (in that it was not present at the 5 s baseline ITI) an impulsive phenotype in the young tauV337M mice at the longest 8 s, ITI (GENOTYPE x TASK MANIPULATION, F3,116 = 4.41, P < 0.01). The effects of increasing the ITI on premature responding were exacerbated in the old tauV337M mice (GENOTYPE x AGE, F1,168 = 8.31, P < 0.01), which showed an augmented and progressive sensitivity to increasing the ITI (GENOTYPE x TASK MANIPULATION, F3,52 = 4.13, P < 0.02). These effects were highly specific to the component of behaviour related to impulsive responding. Increasing the length of the ITI had no effect on either the length of time taken to correctly respond to the stimulus (Fig. 4B, effect of TASK MANIPULATION, F3,196 = 0.67, n.s.) or response accuracy (Fig. 4C, effect of TASK MANIPULATION, F3,196 = 1.06, n.s.) although a general trend towards slower reaction times and reduced accuracy with age, similar to that seen at baseline, was present. Figure 5 shows the effects of reducing the ITI. As anticipated, this task manipulation had the general effect of reducing levels of premature responding irrespective of genotype or age (Fig. 5A, effect of TASK MANIPULATION, F3,168 = 8.66, P < 0.001) but the older tauV337M mice continued to maintain a higher level of premature responses at the 4 and 5 s ITI. As with lengthening the ITI, shorter ITIs were without effect on correct reaction times and discriminative accuracy, apart from a general tendency for the older mice to be slower and less accurate (Fig. 5B and C).


Figure 4
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  		Figure 4. Effects of increasing the ITI on 5-CSRTT performance Once stable baseline performance had been achieved, wild-type (WT) and tauV337M (Tau) mice were tested in a session in which stimulus predictability was disrupted by pseudo-randomly varying the ITI from 5 to 8 s. The number of premature responses performed by both genotypes increased with ITI, however this effect was accentuated in the older tauV337M mice (A). There were no effects of genotype or age on correct reaction time (B). Response accuracy was generally reduced with increasing ITI across all groups (C). Data are the mean for each group (±SEM; wild-type n = 15, young tauV337M n = 15, old wild-type n = 7, old tauV337M n = 8).

 


Figure 5
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  		Figure 5. Effects of decreasing the ITI on 5-CSRTT performance Wild-type (WT) and tauV337M (Tau) mice were tested in a session in which the ITI was reduced in length, pseudo-randomly varying between 2 and 5 s. Although the number of premature responses performed by both genotypes fell with decreasing ITI, old tauV337M mice still performed a small but significant number of premature responses (A). There were no effects of genotype on correct reaction time (B) or response accuracy (C). Data are the mean for each group (±SEM; wild-type n = 15, young tauV337M n = 15, old wild-type n = 7, old tauV337M n = 8).

 
The effects of increasing attentional load in the task were assessed by reducing the stimulus duration. As predicted, discriminative accuracy was progressively impaired with reducing duration (Fig. 6A; effect of TASK MANIPULATION, F3,168 = 14.87, P < 0.001). However, again these effects were indifferent to genotype (GENOTYPE, F1,168 = 2.9, n.s) and only showed the general subtle impairing effects of age (although there was a trend for the older tauV337M mice to be more sensitive to the reductions in stimulus duration) as did the data for speed of responding (Fig. 6B). There were, however, significant effects of reduced stimulus duration on premature responding (Fig. 6C) with the older tauV337M mice making more premature errors under these conditions (GENOTYPE x AGE, F3,168 = 14.3, P < 0.001).


Figure 6
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  		Figure 6. Effects of reducing the stimulus duration on 5-CSRTT performance in a session in which the stimulus duration was reduced in length, pseudo-randomly varying between 0.2 and 0.s, response accuracy was found to fall with stimulus duration, an effect exacerbated by age but not genotype (A). The number of premature responses performed by old tauV337M mice was significantly increased (C). There were no effects on correct reaction time (B). Data are the mean for each group (±SEM; wild-type n = 15, young tauV337M n = 15, old wild-type n = 7, old tauV337M n = 8).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
The main findings of this study were a marked increase in premature responding in the 5-CSRTT shown by mice expressing the human FTDP-17 V337M (valine to methionine) tau mutation (9) in brain. The effects of the transgene expression on baseline impulsive responding were age-related, being present at age 24 months but not 10 months, although manipulation of baseline conditions by increasing the ITI also produced significant differences in impulsive responding in young tauV337M relative to wild-type littermates. The data showed a high degree of behavioural specificity, occurring in the absence of genotype effects on behaviours relating to attention and speed of responding, as well as more general aspects of behaviour including motivation and the basic behavioural strategy used by the mice to perform the task. In particular, in the present work, we were able to conduct a longitudinal behavioural analysis without the major confounding influence of the severe motoric deficits observed in other mouse models of human brain tauopathy, most notably those expressing the P301L and P301S mutations (4,5). Our mouse model expressing the tauV337M mutation, under the control of the murine Thy1 promoter, exhibited no evidence of motoric deficits up to 24 months of age, the latest time point studied. The reason for the preservation of motor function in these mice relative to other FTDP-17 tau models is not entirely clear, although it seems likely to be related to the nature of the specific tau mutation introduced (25,26) and/or the promoter used to control transgene expression, leading to differences in how much, and where, the transgene is expressed in the brain. One key difference identified between the tauV337M mice used in the current study and the tauP301S line of mice [which are under the control of the same promoter but exhibit severe motor abnormalities (5)] was in the levels and distribution of sarkosyl insoluble PHF tau within the central nervous system. The tauP301S mice had, in general, much higher levels of PHF tau and a much wider distribution throughout the brain. Evidence of PHF tau in the tauV337M mice was limited to the forebrain region, whereas, in contrast, PHF tau was found throughout the brain and spinal cord of the tauP301S line. The presence of the established neuropathological marker PHF tau within the hindbrain and spinal cord, especially, may be an important indicator of the likelihood of deficits in motor function.

Several brain systems contribute to the control of response inhibition (17,27), and although work in mice is limited (16,28), studies in rats and humans highlight the importance of the frontostriatal circuitry in mediating the ability to withhold inappropriate responding when a delay has to be negotiated prior to the execution of a motor action (17). Dysfunction of this form of response control can result in impulsive responding [categorized as actions that are poorly conceived, prematurely expressed, unduly risky or inappropriate to the situation and that often result in undesirable outcomes (reviewed in 29)] and may contribute to a number of psychological disorders (30–32). With specific reference to the 5-CSRTT, in the rat, lesions of the anterior cingulate (33) and infralimbic (34) cortices have been shown to increase premature responding, while having no effect on response accuracy, a pattern of effects similar to that seen in the tauV337M mice. As the tauV337M mice showed particularly high levels of transgene expression and abnormal tau phosphorylation in frontal cortex, as well as the presence of sarkosyl insoluble PHF tau in forebrain extracts encompassing the frontal cortex, it may be that the trangene-induced influence on premature responding is mediated, at least in part, by effects in these same brain regions. The specificity of the transgene effects to frontal regions is further suggested by the qualitatively different effects of striatal lesions on behaviour in the 5-CSRTT (35); as illustrated in Figure 1, expression of the tau transgene was minimal in striatum.

The cellular basis by which the expression of the V337M mutated tau transgene influences brain and behavioural functioning is not known. There is evidence in another tauV337M mouse line for neurodegeneration in brain (6,7), and it may be that the increase in impulsive responding reflects brain cell loss. This explanation would be consistent with the age-dependent nature of the behavioural deficit, whereby there may have been a progressive accumulation of damage as the mice aged. Alternatively and/or in addition, the mutated tau may be influencing the neurochemical balance of the brain. Here, an interesting possibility is raised by evidence linking experimental and clinical tauopathies with 5-hydroxytryptamine (5HT), a neuromodulator playing a key and well-established role in behavioural inhibition (27,36), and specifically in premature responding in the 5-CSRTT (17). Using a different FTDP-17 mutation, Egashira et al. (37) showed that tauR406W mice exhibited decreased levels of 5HT and 5-hydroxyindoleacetic acid (a metabolite of 5HT) in the frontal cortex. Treatment of the tauR406W mice with the selective serotonin reuptake inhibitor (SSRI) fluvoxamine normalized brain 5HT levels to that shown by wild-type controls. In patients, there is also some evidence to suggest that the SSRIs trazodone and paroxetine are beneficial in the treatment of behavioural symptoms of FTD, including disinhibition/impulsivity (38–40). The idea that disruptions in 5HT function may be contributing to the impulsive phenotype seen in the tauV337M mice is, a priori, also consistent with some degree of overlap between the 5HT neural system and transgene expression, especially in the frontal cortex, though the overlap is not complete (Fig. 1). Furthermore, impulsivity is not a unitary construct, and it is important to note that other neural systems, especially dopamine (36), play important roles in response inhibition.

Our findings in the tauV337M mouse line recapitulate abnormalities in impulsive responding linked to the FTDP-17 tau V337M mutation in humans. Members of the original Seattle Family A cohort showed a wide range of impulsive and maladaptive behaviours including stealing and shoplifting and outbursts of verbal and physical aggression (10). Similar behavioural changes are also present in fvFTDs that are unrelated to specific tau mutations (11,12). Our study did not provide any evidence of attentional deficits in the tauV337M mice as indexed by discriminative accuracy performance either under baseline conditions or using task manipulations that increased attentional demands, such as reducing the stimulus duration (17) (although older tauV337M mice did show a trend for reduced discriminative accuracy with decreasing stimulus duration). Evidence of early and pre-symptomatic attentional deficits has been identified in patients with the N279K FTDP-17 mutation (41) and FTD (13,14) using tasks designed to assay divided attention, preparatory attention and attentional set shifting. It may be that our model fails to show this aspect of the phenotype or that it will be revealed using other tests of attention rather that the 5-CSRTT. Similarly, it would be relevant to test the tauV337M model in behavioural paradigms that index other forms of response inhibition, such as delayed reinforcement (42,43) in order to assess the generality of the deficits in impulse control.

In conclusion, we report longitudinal data showing age-related increases in impulsive responding in a mouse model of the FTDP-17 V337M tau mutation. Importantly, the data were not confounded by motor abnormalities. We suggest that changes in 5HT function may be important in mediating the abnormal behavioural phenotype. The tauV337M mouse line may have some utility in modelling long-term alterations in cognitive and behavioural function and relating them to abnormal tau function in the brain.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Transgenic mice
Site-directed mutagenesis was used to introduce the V337M mutation into cDNA encoding the longest three-repeat human tau isoform into murine brain-specific modified Thy1 genomic expression vectors at a Xho1 site. A Kozak consensus sequence had been introduced upstream of the initiation codon. TauV337M transgenic mice were produced by pronuclear injection of (C57BL/6J x CBA/Ca) F1 embryos. Founders were identified by PCR analysis of lysates from tail biopsies using the primer pairs 5'-GGTTTTTGCTGGAATCCTGG-3' and 5'-GGAGTTCGAAGTGATGGAAG-3' and founder animals inter-crossed with C57BL/6J x CBA/Ca F1 mice to establish experimental lines. The experimental groups for the study comprised male tauV337M hemizygotes and wild-type littermate controls. Animals were group housed with littermates (two to five animals per cage), subject to a 12 h light/dark cycle (lights on at 7 a.m.), and had ad libitum access to food and water unless stated otherwise.

In situ hybridization
Brain sections from tauV337M (n = 4) and littermate wild-type mice (n = 4), cut in the sagittal plane at 12 mm and mounted on poly-L-lysine-coated slides, were fixed in 4% paraformaldehyde, washed in phosphate-buffered saline and stored in 95% ethanol at 4°C until use. Prior to hybridization, slides were washed in 1x saline sodium citrate (SSC) with 20 mm ß-mercaptoethanol, first at 20°C and then at 55°C, dehydrated in an ascending ethanol series and finally dried. Sections were labelled using specific radiolabelled oligonucleotide probes hybridizing to unique sequences within both transgene and endogenous tau mRNA transcripts: 5'-CTTGGGCTCCCGGGTGGGTGGGGTTGGTTGGGACGGGGTGCGGGAG-3' (human tau) and 5'-CTTGGGCTCCCGGGTGGGCGGTGTTGGTAGGGATGGGGTGCGCGAG-3' (mouse tau).

Each probe was 3' end-labelled using terminal transferase and d-ATP-[35S] and used at 350 000 c.p.m./µl. Sections were hybridized overnight at 55°C in 50% formamide hybridization mixture. The slides were washed in 2x SSC/0.1% sodium dodecyl sulphate (SDS), RNAse treated (10 mg/ml) and dehydrated in an ascending ethanol series as before. Labelled sections and radioactive standards ([14C]microstandards, Amersham, UK) were exposed to X-ray film for 25 days.

Brain homogenate sample preparation
Sagittally dissected brain hemispheres, further dissected into forebrain (including olfactory bulbs, cerebral cortex and hippocampus) and hindbrain (including pons, cerebellum and brainstem) were homogenized in a cocktail of proteinase and phosphatase inhibitors [20 mM Tris–HCl (pH 7.4), 1 mM ethylene glycol-bis(2-aminoethyl)-N,N,N',N',-tetraacetic acid (EGTA), 1% Triton, 1% pyrophosphate, 1% orthovanadate,1% beta-glycophosphate, 5% NaF, protease inhibitor tablet (Boehringer Mannheim, Germany)]. The protein concentration of each sample was determined using a bicinchoninic acid protein assay kit (Pierce, USA). The protein concentration of samples were normalized to 8 µg/µl by dilution in homogenization buffer and then diluted 1:1 in sample buffer [250 mM Tris base, 16% (w/v) SDS, 30% (v/v) glycerol, 15% (v/v) (-mercaptoethanol, and 3% bromophenol blue (pH 8.7) so that the final concentration was 4 µg/µl.

PHF tau extraction
PHF tau was extracted from spinal cord and sagittally dissected brain hemispheres (n = 3 for both tauV337M and littermate wild-type mice), further dissected into forebrain and hindbrain, according to the methods described previously (Greenberg and Davies, 1990) (44). Tissue was homogenized in 10 mM Tris/HCl pH 7.4, 800 mM NaCl, 1 mM EGTA, 10% sucrose, spun at 14 000g at 4°C and the supernatant collected. The pellet was resuspended, homogenized again and the supernatants pooled. N-lauroylsarcosine (Sigma) was added to 1% final concentration and the mixture left shaking for 1 h at room temperature. Following ultracentrifugation at 100 000g for 1 h at 20°C, the pellet was resuspended in 50 mM Tris/HCl, pH 7.4. Samples were diluted in sample buffer [250 mM Tris base, 16% (w/v) SDS, 30% (v/v) glycerol, 15% (v/v) (-mercaptoethanol and 3% bromophenol blue, pH 8.7].

Western blotting
Samples were run by standard SDS–PAGE methodology on 10% polyacrylamide gels and transferred onto nitrocellulose membrane by semi-dry transfer. Nitrocellulose membrane blots were probed using a primary antibody to human tau (T14 clone, 1:1000 dilution, Zymed, USA). Blots were probed with peroxidase-labelled secondary antibody (Amersham Pharmacia Biotech) and visualized using ECLTM-Plus Western blotting detection reagent (Amersham Pharmacia Biotech).

Immunohistochemical and histological studies
Brain sections from transcardially perfused animals (n = 4 for both tauV337M and littermate wild-type mice), cut in the sagittal plane at 30 µm, were stained using standard immunohistochemical techniques, following blocking of endogenous peroxidase activity (20% methanol, 1.5% hydrogen peroxide) and incubation in MOM Ig blocking reagent (Vector Labs, USA). Free-floating sagittal sections (30 mM) were incubated overnight at 4°C with primary monoclonal antibodies to human tau (T14 clone; Zymed) and phospho-S202/T205 tau (AT8 epitope, Innogenetics). Reagents and biotinylated secondary antibody from a Vector MOM immunodetection kit (Vector Labs) were used and immunoreactivity identified by a diaminobenzidine tetrachloride reaction (Vector Labs).

Bielschowsky staining was performed on slide-mounted sagittal sections from transcardially perfused animals (15 mm thickness). Slides were incubated in 20% silver nitrate solution for 2 h, washed in reducer (50 ml formaldehyde, 200 ml absolute alcohol, 750 ml distilled water) for 3 min, followed by 10% alcohol for 2 min. Slides were placed in Silver B solution (20 ml 20% silver nitrate, 20 ml 95% alcohol, ammonia added until precipitate formed was redissolved) for 2min, then washed in a constant flow of reducer for 4 min. Following washing in distilled water, slides were toned with 0.1% gold chloride for 2 min, washed in distilled water and fixed in 5% sodium thiosulphate.

Longitudinal behavioural testing
Prior to any behavioural testing, the mice were handled daily for 2 weeks and body weights monitored. Standard lab chow and water were available to mice ad libitum, with the exception of during 5-CSRTT testing, when mice were maintained on a restricted water regime of 2 h water per day (16,19). Regular health checks and weighing ensured that mice were not adversely affected by this schedule, as required by the UK Home Office project licence conditions. Mice were approximately 4 months of age at the start of 5-CSRTT shaping and training, 6 months of age at baseline and 10 months of age when all task manipulations were completed. Re-testing in the 5-CSRTT began when mice were aged approximately 24 months of age and was completed by 26 months of age (details of shaping, training and re-training in young and old mice are discussed subsequently). Eight wild-type and seven tauV337M of the 5-CSRTT group died before re-testing at 24 months. Parallel, longitudinal testing of a separate cohort of mice on the rotarod and LMA apparatus took place at 6 and 24 months of age.

Motor function
Rotarod testing was used to assess motor co-ordination and balance (Rotarod 7650: Accelerating model, Ugo Basile, Biological Research Apparatus, Varese, Italy) (45). Mice received two training sessions of four trials at 10–15 r.p.m., sufficient to reach a baseline level of performance. The following day, mice were tested at six speeds, ranging from 10 to 44 r.p.m. During training and test sessions, the latency to fall at each speed was recorded up to a maximum of 60 s. LMA testing took place in clear Perspex boxes containing two transverse infrared beams, spaced equally along the length of the box. Sessions were run under red lighting conditions and the number of beam breaks during a 120 min session recorded as described previously (16).

Reinforcer preference
Before testing began in the 5-CSRRT, the preference of the subjects to choose the condensed milk reinforcer to be used in the task was assessed. Testing was carried out as described previously (16,19), with the main index of preference being the amount of reinforcer (10% condensed milk solution, Nestle Ltd, Croydon, UK) drunk on the final day of testing as a percentage of total fluid consumption (tap water versus reinforcer).

5-CSRTT apparatus, behavioural shaping and trial design
The use of the 5-CSRTT to assay aspects of attention and impulse control in mice has been fully described elsewhere (16,19). Testing took place in a nine-hole box modified for use in mice, with four alternate holes in the horizontal array covered. Shaping involved training mice to press a Perspex panel opposite the array of holes in order to gain access to reinforcer. During the 5-CSRTT, trials were initiated by a panel push. This resulted in a 5 s ITI after which a stimulus light was randomly presented in one of the five uncovered holes. A nose poke by the mouse in the illuminated hole (i.e. a correct response) resulted in the presentation of 20 µl of reinforcer behind the Perspex panel and collection of this reward initiated a second trial. An incorrect response (i.e. a response in a hole in which a light was not presented), an omission (i.e. no response during the duration of the stimulus +5 s) or a premature response (i.e. a nose poke prior to the onset of a stimulus light) resulted in a 5 s time out period in which the ‘house lights’ were illuminated. The time out period could be terminated through a panel push, which started a new trial.

Training to baseline performance
Immediately following shaping, the stimulus duration was set for 32 s; this was gradually reduced to a baseline stimulus duration of 0.8 s in the sequence 32, 16, 8, 4, 2, 1.8, 1.6, 1.4, 1.2, 1.0 and 0.8 s. The stimulus duration for a given mouse was reduced to the next level once it had met performance criteria over two consecutive days (>50 completed trials, >80% accuracy, i.e. ratio of correct:total responses, and <20% omissions, i.e. no response to <20% of all trials initiated); during the course of training, no other parameters were altered. Baseline acquisition performance was set as criterion performance observed at a stimulus duration of 0.8 s. For the re-acquisition sessions, conducted at 24 months of age, the mice were reintroduced to the task at 4 s stimulus duration. This was then reduced to the baseline stimulus duration of 0.8 s according to the same performance criteria used previously.

Task manipulations at stable baseline
Upon stabilization of baseline performance, a variety of task manipulations designed to influence dissociable aspects of attention and response control were performed. Each manipulation was performed after 2 consecutive days of stable baseline performance. The 5-CSRTT manipulations were performed in the following order: ‘long ITI’ (of 5, 6, 7 and 8 s), ‘short ITI’ (of 2, 3, 4 and 5 s) and reduced stimulus durations (of 0.2, 0.4, 0.6 and 0.8 s). On manipulation sessions, the various parameters were presented pseudo-randomly.

Behavioural measures
The following measures were recorded both from initial acquisition of the task(s) at 4 months of age and following task re-acquisition at 24 months of age: total number of trials per session, discriminative response accuracy (the primary measure of attention), % omissions (reflecting possible failures of detection and/or motivational/motor deficits), number of premature responses, (indexing aspects of impulse control), correct reaction time (defined as latency to nose poke in the correct hole after stimulus presentation), latency of eating (time taken to collect reward after a correct response), duration of eating (time spent in the food magazine after a correct response), total number of nose pokes and total number of panel pushes. The number of nose pokes and panel pushes per completed trial were calculated as indices of general performance efficiency.

Statistics
All statistics were analysed using the SAS statistical package (SAS Institute Inc., USA). Rotarod and LMA data were assessed by ANOVA with factors GENOTYPE (wild-type and tauV337M) and AGE (young, 6–10 months; old, 24–26 months). Data from the condensed milk reinforcer habituation/preference test were analysed by ANOVA for total volume consumed and percentage condensed milk preference with factor GENOTYPE. Acquisition and re-acquisition data for the 5-CSRTT were analysed by ANOVA with factors GENOTYPE, AGE and TRAINING LEVEL (32, 16, 8, 4, 2, 1.8, 1.6, 1.4, 1.2, 1.0, second stimulus duration). Baseline performance data were analysed by ANOVA with factors GENOTYPE and AGE. The effects of the various task manipulations were assessed by ANOVA with factors GENOTYPE, AGE and TASK MANIPULATION (long ITI, short ITI, reduced stimulus duration). Percentage differences were subject to an arcsine transformation prior to ANOVA in order to normalize the data [skewed data can result from high levels of performance shown by subjects in the 5-CSRTT relative to the 100% maximum (46)]. Where significant interactions were identified in the main ANOVA, post hoc testing using Tukey's test for pairwise differences was carried out.


   ACKNOWLEDGEMENTS
 
We gratefully acknowledge Dr M. Goedert (Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, UK) for supplying the tauV337M mice, Dr R. Raha-Chowdhury for assistance with tau immunohistochemical staining and PHF tau preparations (Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, UK) and Dr W. Davies for critical reading of the manuscript. This work was supported by the Biotechnology and Biological Sciences Research Council UK and the Alzheimer's Research Trust UK. S.L.L. is the recipient of an Alzheimer's Research Trust Research Fellowship.

Conflict of Interest statement. None declared.


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TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
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