Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses
© Rudinskiy et al.; licensee BioMed Central Ltd. 2014
Received: 21 May 2014
Accepted: 21 May 2014
Published: 10 June 2014
Intraneuronal neurofibrillary tangles (NFTs) – a characteristic pathological feature of Alzheimer’s and several other neurodegenerative diseases – are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.
Intraneuronal neurofibrillary tangles (NFT) composed of misfolded hyperphosphorylated tau proteins are one of two stereotypical types of lesions present in the Alzheimer’s brain (together with amyloid plaques) . The extent of neurofibrillary pathology correlates well with synaptic loss, neuronal loss, glial activation, and cognitive decline  and tangles have long been considered a primary therapeutic target in Alzheimer’s disease (AD). Moreover, mutations in tau have been linked to neurodegeneration in several tauopathies, including FTDP-17 , and cerebral tau aggregates are present in many disorders .
Despite the compelling proof for a role of misfolded tau in neurodegenerative disease, little data directly test the hypothesis that tangles, per se, impair neuronal function. In fact, there is no conclusive evidence for a mechanistic role of NFTs in dysregulation of nervous system, either on a single-neuron or neuronal network level. We hypothesized that the tangle pathology would disrupt integration of incoming information in individual neurons with NFTs and that the brain networks most affected by tangles would have impaired neuroplastic properties when responding to sensory inputs in vivo. As a proxy of experience-dependent network integration and plasticity we used the activity-dependent transcription of a memory-related immediate-early gene Arc. Activity-driven expression of Arc is crucial for synaptic tagging and remodeling in response to sensory and behavioral inputs (reviewed in [5–9]) and is often used as a reporter of expression of neuroplasticity in excitatory neurons.
We quantitatively assessed the impact of tangle pathology on the experience-driven Arc responses after a behaviorally relevant, well characterized visual stimulus paradigm [10–13] to determine whether there are cell-specific or network-wide plasticity deficits directly linked to NFTs. We crossed the rTg4510 mice which express P301L mutant form of human tau and develop advanced tangle pathology , with a previously characterized fluorescent reporter line of Arc transcription [10, 15]. Using intravital fluorescent brain microscopy we found that the presence of NFTs in visual cortex neurons did not affect the amplitude of Arc responses to the stimulation. Postmortem odds ratio analysis revealed that the probability of Arc response in individual neurons in both visual cortex and hippocampus is not affected by expression of mutant tau and/or presence of tau tangles. Quantitative analysis of all brain regions with detectable neuronal Arc expression after visual stimulation showed no differences in characteristics of network-wide Arc responses between control and mutant mice, even in the brain areas with the highest tangle load. Finally, reduction of brain-wide soluble human tau concentration by suppression of mutant tau expression in the rTg4510 mice did not affect Arc responses. These results indicate that behavioral and physiological deficits observed in mice expressing P301L mutant of human tau are not mediated by alterations of post-synaptic pathways involved in activity-dependent expression of immediate-early genes such as Arc.
Tau pathology does not affect the amplitude of experience-driven Arc responses in the visual cortex
NFTs do not change the probability of Arc response in the host neurons
Tau pathology does not affect brain-wide Arc responses
Previous studies have shown that the expression of soluble mutant tau is largely responsible for behavioral and physiological deficits and neurotoxicity in the rTg4510 model [14, 27]. We took advantage of the fact that the transgene expression in the rTg4510 mice can be suppressed by doxycyclin treatment [14, 21, 27] to determine whether removal of soluble mutant tau in aged mice affects brain-wide Arc responses. A cohort of 11–12 months old transgenic and control littermate mice received doxycycline-supplemented diet for 6 week, after which they underwent visual stimulation as described above and their brains were processed for the brain-wide Arc::dVenus expression analysis. We found no effect of doxycycline treatment on activity-driven Arc responses in either control or transgenic mice in none of brain regions with consistent detectable Arc expression (Figure 4).
This study aimed to elucidate the effects of tau pathology on experience-dependent neuroplasticity in individual neurons and local neuronal networks. We applied an experimental paradigm that we have recently developed to address a similar question in the context of Aβ pathology . Reporter mice expressing a fluorescent protein under the control of the plasticity-related immediate-early gene Arc promoter  were crossed to a model of tauopathy based on P301L mutation in the human tau protein . We studied experience-induced Arc reporter expression in the brains of these mice with a combination of in vivo longitudinal multiphoton imaging and postmortem immunohistochemical analysis. Using quantitative in vivo measurements of Arc transcription reporter followed by detection of NFTs in large volumes of the visual cortex of a living mouse brain, we showed that tangles did not affect the absolute Arc expression levels in the individual responses of neurons. At the same time, neurons with NFTs were as likely to have Arc responses as neurons without NFTs, as determined postmortem in the same brain area. Similar to visual cortex neurons, CA1 pyramidals with NFTs had the same likelihood of Arc responses as their neighbors without tangles. Taking into account the complex postsynaptic signaling and transcriptional machinery required for the activity-driven expression of the Arc gene [7, 8, 28–30], this demonstrates, for the first time, that despite being large cytoplasmic space-occupying inclusions, NFTs do not significantly disrupt the integration of synaptic inputs and the downstream execution of memory-related genetic programs. The data also do not demonstrate any changes in Arc responses to a sensory stimulus due to the soluble mutant tau ubiquitously expressed in the CamKII-positive neurons in this mouse model. There is a possibility that NFTs or tau indeed introduce changes to Arc responses small enough that they could not be detected with our imaging and analysis methods. However, in our previous study using this quantification technique with similar cohort sizes (and thousands of neurons examined)  we were able to resolve significant changes as small as 15% of median expression level postmortem and 25% in vivo. It is unlikely that if smaller undetected changes were induced by NFTs, they would have significant effect on neuronal circuit function, as these changes would be orders of magnitude lower than Arc responses to physiological stimuli [10, 11]. These conclusions are in accord with a recent study from our laboratory showing intact function of tangle-bearing and tangle-free neurons in the visual cortex of rTg4510 mice as demonstrated by in vivo multiphoton imaging of visual activity-evoked calcium transients .
Our findings of unchanged Arc transcription in the visual cortex contrasted with a previous study from our laboratory showing decreased Arc expression in the CA1 pyramidal layer of the hippocampus in the rTg4510 model mice after exploration of a novel environment  and with the earlier mRNA profiling of the human AD brains which found lower amounts of the Arc mRNA in tangle-bearing CA1 neurons compared to tangle-free neurons . To gain a “brain-wide” perspective on the tau pathology effect on neuronal networks, we processed entire brains of rTg4510 mice crossed with Arc reporter strain to identify anatomical regions with detectable Arc expression following the exposure of the mice to the structured visual stimulation. We found no regions that lacked activation in one genotype and were active in the other and vice versa, which indicates that the widespread tau pathology does not fundamentally change brain wiring patterns. We also detected no overt differences in experience-dependent network-wide Arc expression levels between transgenic mice and control littermates in any of the examined brain regions. Even the brain areas with the highest tangle load (such as CA1 field of the hippocampus where more than 50% of the brain section was occupied by tangles) exhibited normal Arc responses to the visual stimulation.
We considered the differences in experimental paradigm between the initial study of hippocampal responses to exploration of a novel environment  and the current study, which focused on visual cortical responses to defined visual stimuli. Since the retina and lateral geniculate are disease free in this model, the latter stimulus was designed to specifically probe somatodendritic responses and integration of signals in which the axons carrying the primary input are intact, while the behavioral/memory aspects of the exploratory behavior task requires integration of widely dispersed information in the cortex and concurrent signaling to the hippocampus for further processing from areas that are markedly impacted by both NFT and neuronal loss. It may be that this latter form of integrative function is more dependent on the integrity of axonal processes and on the relative timing and intensity of feedforward and feedback signals, and so Arc reporting of signal in the hippocampus is inherently more sensitive to subtle effects compared to visual cortical responses. Nonetheless, the agreement between the studies that the presence of NFT does not impact the likelihood of an Arc response, despite the substantially different behavioral paradigms and the method of assessing Arc (in situ hybridization v.s. Arc promoter-driven fluorescent reporter) emphasizes that the type of defect in signal integration caused by a tangle, if any, is quite subtle.
Overall, our findings show that NFTs do not significantly alter postsynaptic function of the host neurons which is required for the experience-dependent Arc expression. Given the importance of meticulous Arc regulation for the proper functioning of synaptic machinery [33–36] and the role that activity-dependent Arc expression plays in memory-related physiology through AMPAR endocytosis , structural plasticity  and synaptic tagging , our data suggest that mechanisms not linked to experience-dependent immediate early genes are behind behavioral phenotypes in rTg4510 mice and cognitive impairment in AD. A number of studies have demonstrated electrophysiological, functional and morphological changes in neurons from rTg4510 mice at the advanced stage of tau pathology [28, 39–42], and, notably, increased intrinsic excitability in the cortical neurons, with evidence indicating that these changes could not be attributed to the presence or absence of NFTs in the affected neurons [40, 42]. Taken together with our data, NFTs appear not to cause major disruptions of synaptic integration of information.
Materials and methods
All animal experimentation was performed in conformance with institutional and US National Institutes of Health guidelines and approved by the Massachusetts General Hospital Institutional Animal Care and Use Committee. Arc::dVenus reporter mice expressing destabilized variant of a bright yellow fluorescent protein dVenus under 7.1 kb mouse Arc promoter  were crossed with suppressible CamKII::rtTA × tetO::Tau (P301L) (rTg4510) strain . Arc::dVenus × CamKII::rtTA non-carriers of Tau (P301L) transgene were used as littermate controls to account for potential effects of rtTA transactivator overexpression. Genotyping was performed using polymerase chain reaction (PCR) with three pairs of primers targeting dVenus, rtTA and Tau (P301L). For mutant tau suppression experiment, a cohort of mice (n = 5 control, n = 3 transgenic) was fed chow containing 200 mg/kg doxycycline (Harlan Teklad) for 6 weeks before visual stimulation. All mice used in this study were 11–13 months old.
Visual stimulation, surgery and in vivo multiphoton imaging
Structured visual stimulation was performed as described previously . Briefly, single-housed mice were placed in their home cages into the dark light-proof ventilated enclosures for 60 hours prior to beginning of stimulation to suppress visual experience-induced Arc::dVenus expression. After the end of light deprivation mice were transferred to an illuminated glass cylinder with alternating vertical black and white stripes for 1 hour. Following the end of the visual stimulation, mice were placed back into the home cages and put into light deprivation chambers for 5 hours before the anesthesia for cranial window implantation was induced with 4% isoflurane in balanced oxygen inside of the dark light-proof enclosure for 5 minutes and maintained at the level of 1.2–1.6% during the surgery and consequent imaging while keeping the body temperature at 37°C. Cranial windows were implanted over the right visual cortex as described previously [10, 43]. Immediately after cranial window implantation Texas Red-conjugated dextran (MW 70,000 Da, 12.5 mg/mL in sterile PBS, Molecular Probes) was injected IV to provide fluorescent angiogram used as landmark pattern for co-registration of two consecutive imaging sessions and as a reference fluorophore to monitor cranial window clarity and appearance of bleedings. Mice were imaged on multiphoton Olympus Fluoview 1000 MPE system equipped with mode-locked titanium/sapphire MaiTai laser (Spectra-Physics) and Olympus BX61WI upright microscope with XLPLN 25× water-immersion objective (NA = 1.05). Z-stacks in both imaging sessions were acquired with the resolution of 1 μm/pixel in X-Y dimension with the Z-step of 3 μm. For each mouse the imaged site consisted of 2×4 512×512×240 μm stacks acquired with 10% overlap in X–Y dimensions resulting in an imaged field in visual cortex spanning roughly 1×2×0.24 mm3 ((m–l) × (r–c) × (d–v)). For the first imaging session, excitation laser was tuned to 860 nm with the output power set to 76 mW before the objective. Emitted light was collected in three channels: 460–500 nm (autofluorescence), 530–560 nm (dVenus fluorescence) and 575–630 nm (Texas Red dextran angiogram). Then, methoxy-X04 (5 mg/kg)  diluted in Texas Red dextran solution (12.5 mg/mL in sterile PBS) was injected IV to label NFTs. 30 minutes after methoxy-X04 injection, a second imaging of the same site was performed with the excitation laser tuned to 800 nm for more efficient detection of metoxy-X04 fluorescence, with 100 mW output power before the objective. In this session, the 460–500 nm channel collected emitted light from methoxy-X04 bound to the tangles and other two channels contained the same dVenus and Texas Red dextran signals as in the first sessions and were used for consequent co-registration of the two image stacks. Imaging settings were kept constant between mice and the laser output power was calibrated before each imaging session using infrared photometer.
Processing and quantification of in vivo imaging data
Only image stacks acquired during the first imaging session (860 nm excitation, before methoxy-X04 injection) were used for quantification of Arc::dVenus expression levels to avoid potential spectral crosstalk with methoxy-X04. Arc::dVenus expression levels were processed using Fiji package of NIH ImageJ software (fiji.sc; rsbweb.nih.gov/ij) as described previously . Both stacks (before and after methoxy-X04 injection) were aligned side-by-side based on dVenus and Texas Red dextran patterns (as on Figure 1d) and each quantified dVenus-positive neuron was manually assigned a tangle-positive or tangle-negative status.
Post-mortem tissue analysis
After the end of in vivo imaging still anesthetized mice were transcardially perfused with ice-cold phosphate-buffered saline (PBS) followed by 4% paraformaldehyde in PBS. Brains were incubated in fixative at 4°C for 48 hours and 50 μm free-floating sections were cut on a Microm HM400 microtome. Coronal sections were consecutively collected into 10 tubes, so each tube contained a set of sections covering the full forebrain with 500 μm interval. For the cell counting, appropriate sections were first incubated in thiazine red (MP Biomedicals, 0.01% in PBS) for 20 min to label NTFs and washed 3 times with PBS, followed by immunolabeling with mouse anti-NeuN antibody (1:500, Cat. No MAB377, Millipore) and secondary goat-anti-mouse AlexaFluor 350 (1:500, Cat. No A11045, Molecular Probes). Stereological counting of Arc::dVenus- and NeuN-positive neurons was performed on Olympus CAST system in neuronal layer II/III of medial extrastriate visual cortex and pyramidal layer of CA1 field of the hippocampus. Images for Figure 2 were acquired on Zeiss Axio Observer. Z1 fluorescent microscope equipped with 40× objective. For the full-brain analysis, an entire set of sections spaced at 500 μm from each mouse was labeled with thiazine red mixed with DAPI (0.2 μg/ml), washed for 1 hour in 1% Triton-X100 in PBS and 3 times in PBS. Full-section tile scan was performed on Zeiss Axio Observer. Z1 microscope with 5× objective run by MetaMorph (Molecular Devices) using following three filter sets: Ex/Em 365/445 nm (DAPI), 500/545 nm (direct dVenus fluorescence) and 545/620 (thiazine red). Stitched multichannel images were manually aligned to Allen Mouse Brain Reference atlas (brain-map.org). All image processing was performed in Fiji package of ImageJ. To quantify Arc::dVenus in individual cells, regions of interest with Arc::dVenus-positive neurons in the dVenus channel were cropped to save computation time, background subtracted, images thresholded and segmented with “Analyze particles” plug-in to identify cell bodies. The cell body masks were then applied to the pre-thresholded images to measure mean fluorescence intensity in each identified cell body. To quantify NFT load, brain regions of interest were outlined based on reference atlas alignment and DAPI labeling. Crop masks were applied to the thiazine red channel, images thresholded and percentage of area occupied by tangles calculated.
The normality of all datasets was tested using Kolmogorov-Smirnov method. Non-normal datasets of Arc::dVenus expression levels in individual neurons with variable sample sizes (Figure 1 and 3) were compared using Wilcoxon rank-sum test with correction for clustering of values within individual mice . Comparison of normal data with identical sample sizes (Figure 2c,d) was performed using one-way ANOVA with Bonferroni post-test. The associations between tangles and Arc responses and corresponding odds ratios (Figure 2) were analyzed using 2-way contingency table analysis with Fisher’s exact test (GraphPad Prism 5); this assumes independence across neurons. To assess the effects of doxycycline treatment (Figure 4) we used a mixed effects model to adjust for treatment and genotype and their interaction, with adjustment for correlation within mouse. Each region was modeled separately. We corrected for multiple testing across the eight brain regions using a Bonferroni correction. Calculation of Spearman R and correlation P-value for normal tangle load data with identical sample sizes (Figure 5) was performed on average values across mice.
We thank G.A. Carlson and R. Pitstick (McLaughlin Research Institute, Montana) for providing rTg4510 mice; S. Yamaguchi and M. Eguchi (Gifu University, Japan) for providing the Arc::dVenus reporter line; A. Serrano-Pozo (MGH) for help with statistical analysis; M. Albers (MGH) for helpful discussions. This research is supported by the grants from the US National Institutes of Health (R00AG33670 to T.L.S-J.), AG026249, AG005134 (to B.T.H.), Fidelity Biosciences (to B.T.H.), Alzheimer’s Research UK (to T.L.S-J) and Harvard NeuroDiscovery Center (to R.A.B. and A.M.). N.R. is supported by the fellowships from the Swiss National Science Foundation and the Swiss Foundation for Grants in Biology and Medicine, S.W. is supported by the German Research Foundation (DFG).
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