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Neurofibrillary Tangle-Bearing Neurons Are Functionally Integrated in Cortical Circuits in Vivo

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Neurofibrillary Tangle-Bearing Neurons Are Functionally Integrated in Cortical Circuits in Vivo Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo Kishore V. Kuchibhotlaa,b,1, Susanne Wegmanna,1, Katherine J. Kopeikinaa,c, Jonathan Hawkesa, Nikita Rudinskiya, Mark L. Andermannd, Tara L. Spires-Jonesa,e, Brian J. Bacskaia, and Bradley T. Hymana,2 aAlzheimer’s Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129; bSkirball Institute, NYU School of Medicine, New York, NY 10016; cDepartment of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118; dDivision of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and eCentre for Cognitive and Neural Systems, University of Edinburgh Neuroscience, Edinburgh EH8 9JZ, United Kingdom Edited by Paul Greengard, The Rockefeller University, New York, NY, and approved November 22, 2013 (received for review October 7, 2013) Alzheimer’s disease (AD) is pathologically characterized by the de- selectivity) (17, 18). We further used YC3.6 as a FRET-based position of extracellular amyloid-β plaques and intracellular aggre- ratiometric indicator to make quantitative measurements of gation of tau protein in neurofibrillary tangles (NFTs) (1, 2). resting calcium (15). Resting calcium is tightly regulated in the Progression of NFT pathology is closely correlated with both in- brain, and slight deviations can trigger chronic and severe de- creased neurodegeneration and cognitive decline in AD (3) and generative pathways (15). Thus, measurement of resting calcium other tauopathies, such as frontotemporal dementia (4, 5). The is an important and complementary functional assay for evaluating assumption that mislocalization of tau into the somatodendritic neuronal health. Importantly, performing experiments in awake, compartment (6) and accumulation of fibrillar aggregates in NFTs head-fixed animals eliminates the impact of anesthesia on re- mediates neurodegeneration underlies most current therapeutic sponse properties, resting calcium, and tau aggregation (Fig. 1 A strategies aimed at preventing NFT formation or disrupting exist- B ing NFTs (7, 8). Although several disease-associated mutations and and Movie S1) (19). cause both aggregation of tau and neurodegeneration, whether Results NFTs per se contribute to neuronal and network dysfunction in NEUROSCIENCE vivo is unknown (9). Here we used awake in vivo two-photon We first confirmed that 8- to 10-mo-old control animals exhibi- calcium imaging to monitor neuronal function in adult rTg4510 ted robust orientation and direction selectivity, similar to pre- mice that overexpress a human mutant form of tau (P301L) and vious reports in young and aged mice (20) (Fig. 1 and Fig. 2 B–E, develop cortical NFTs by the age of 7–8 mo (10). Unexpectedly, control traces). Average and single trial traces of responses to NFT-bearing neurons in the visual cortex appeared to be com- visual stimuli measured in a single neuron from a control animal pletely functionally intact, to be capable of integrating dendritic are shown in Fig. 1C. In this example, the neuron (cell 1) pref- inputs and effectively encoding orientation and direction selectiv- erentially responds to a visual stimulus orientation of 225° and ity, and to have a stable baseline resting calcium level. These results has an orientation selectivity index (OSI) of 0.95 and a direction suggest a reevaluation of the common assumption that insoluble selectivity index (DSI) of 0.95 (Fig. 1 C, D, and F; 0 indicates no tau aggregates are sufficient to disrupt neuronal function. selectivity, and 1 indicates perfect selectivity). paired helical filaments | tau pathology | neuronal networks Significance eurofibrillary tangles (NFTs) containing aggregated tau Alzheimer’s disease is pathologically characterized by extra- Nprotein (1) have long been considered key players in the cellular amyloid-β plaques and intracellular neurofibrillary progressive neural dysfunction and neurodegeneration observed ’ tangles (NFTs). It has long been assumed that the accumulation in Alzheimer s disease (AD) (2, 3) and other tauopathies (4, 5). of tau into NFTs causes neuronal dysfunction and death, and is It is commonly assumed that NFT-bearing neurons exhibit def- a proximate cause of dementia in patients with Alzheimer’s icits in synaptic integration and eventually lead to neurodegen- disease. This assumption underlies the NFT-busting drugs cur- eration (11, 12). However, the actual functional properties of rently in clinical trials and research efforts aimed at under- NFT-bearing neurons in intact neural circuits have not been standing tau aggregation. Our study tested the dogma that explored previously (13). We addressed this question directly NFT-bearing neurons are indeed impaired in their ability to using awake in vivo two-photon calcium imaging in a mouse respond to complex sensory stimuli. Using two-photon imag- model of NFT formation (rTg4510) by applying recently devel- – ing in awake mice with NFT pathology, we found that in- oped imaging approaches allowing for single-neuron level and dividual neurons with NFTs respond to visual stimuli and do population-level assessment of neural activity in awake mice (14). not impair local circuits. These unexpected results suggest that Because two-photon calcium imaging allows for measurement of the presence of an NFT does not inevitably lead to gross physi- response properties in many neurons simultaneously, we were able ological alterations. to directly isolate the impact of NFT deposition in a neuronal microcircuit by evaluating population-level network dynamics Author contributions: K.V.K., S.W., T.L.S.-J., B.J.B., and B.T.H. designed research; K.V.K., and, more specifically, by differentiating the function of individual S.W., K.J.K., J.H., and N.R. performed research; K.V.K., S.W., M.L.A., and T.L.S.-J. contrib- NFT-bearing and neighboring non–NFT-bearing neurons. uted new reagents/analytic tools; K.V.K. and S.W. analyzed data; and K.V.K., S.W., B.J.B., To assess the functional properties of neurons in the visual and B.T.H. wrote the paper. cortex, we used a genetically encoded ratiometric calcium in- The authors declare no conflict of interest. dicator, yellow cameleon 3.6 (YC3.6), packaged in an adeno- This article is a PNAS Direct Submission. associated viral vector (15, 16). To assess functional responses, Freely available online through the PNAS open access option. we exploited the well-characterized functional architecture of 1K.V.K. and S.W. contributed equally to this work. visual cortex whereby neurons in mouse visual cortex modulate 2To whom correspondence should be addressed. E-mail: [email protected]. their activity during presentation of drifting gratings moving at This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. specific orientations and directions (orientation and direction 1073/pnas.1318807111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1318807111 PNAS Early Edition | 1of5 Downloaded by guest on September 26, 2021 Fig. 1. YC3.6 calcium imaging in awake cortex of control mice reveals robust visual response tuning. (A) Awake and head-fixed mice expressing AAV-YC3.6 in visual cortex were presented with drifting gratings to record visually evoked calcium responses through a chronic cranial window (Movie S1). (B) In vivo two- photon image of YC3.6-expressing neurons in layer 2/3 (∼180 μm below the brain surface) with four example neurons (white circles). (Scale bar: 50 μm.) (C) Drifting gratings (eight stimulus types, 45° apart) were presented for 7–10 s, followed by 7–10 s without stimulation (gray screen). This sequence was repeated 10 times. For cell 1 (orientation- and direction-selective), three representative single-trial time courses (YFP:CFP ratio) and the average trace across 10 trials reveal its predominant response to a grating direction of 225°. SEM is shown in gray; arrowhead indicates preferred direction. (D) Polar plot of cell 1 demonstrating selectivity of this neuron for the 225° stimuli. (E) Average traces of three other neurons (white circles in A) illustrate the diversity in orientation and direction tuning. Cell 2 is orientation-selective but not direction-selective, cell 3 responds to all directions (broadly tuned), and cell 4 does not respond to any direction (not responding). (F) OSI and DSI for cells 1–4. We next explored the functional response profiles of neurons immediately after completion of in vivo imaging, followed by in the visual cortex of transgenic mice with a significant NFT postmortem immunolabeling of YC3.6 (with anti-GFP antibody), load in the visual cortex at similar ages to control animals (Fig. hyperphosphoryated tau (with PHF1 antibody), and staining 2A and Fig. S1) and compared these profiles with those of of mature NFTs using thioflavin-S (ThioS) in whole brains of neurons from control brains (Fig. 2 B–E). The rTg4510 mice rTg4510 mice (Fig. S4). All ThioS-positive NFT-bearing neurons exhibited numerous NFTs throughout the cortex, including the (n = 32) showed PHF1 labeling of hyperphosphorylated tau, and visual cortex (Fig. 2A), along with behavioral deficits typically very few neurons (n = 6) had hyperphosphorylated tau but no seen at this age (10). We observed a marked uniformity in resting mature NFTs. For statistical analyses of NFT neuron respon- calcium levels across the population of neurons measured in siveness, ThioS stained cells were defined as NFT-bearing neu- B control mice (Fig. 2 ), consistent with previous reports of tightly rons. In a subset of animals, we also labeled NFTs in vivo using i.v. regulated resting calcium concentration in the healthy cortex injections of the Congo red derivate methoxy-X04 in anesthetized (15). Neurons in the rTg4510 mice and control mice exhibited animals (22, 23) (Fig. S5). nearly identical resting calcium profiles (control, 1.32; rTg4510, Remarkably, resting calcium (Fig. 3D) and neuronal tuning P = t n = n = 1.31; cohort-level: 0.84, test, 3 rTg4510 mice, 3 (Fig.
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