Abstract
Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca2+-permeable and Ca2+-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell–derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.
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References
Dickson, D.W. Parkinson's disease and parkinsonism: neuropathology. Cold Spring Harb. Perspect. Med. 2, a009258 (2012).
Goldstein, L.H. & Abrahams, S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 12, 368–380 (2013).
Serrano-Pozo, A., Frosch, M.P., Masliah, E. & Hyman, B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).
Neary, D., Snowden, J. & Mann, D. Frontotemporal dementia. Lancet Neurol. 4, 771–780 (2005).
Loy, C.T., Schofield, P.R., Turner, A.M. & Kwok, J.B. Genetics of dementia. Lancet 383, 828–840 (2014).
Gendron, T.F., Belzil, V.V., Zhang, Y.J. & Petrucelli, L. Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol. 127, 359–376 (2014).
Ling, S.C., Polymenidou, M. & Cleveland, D.W. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416–438 (2013).
Cox, L.E. et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS ONE 5, e9872 (2010).
Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).
Hooli, B.V. et al. Rare autosomal copy number variations in early-onset familial Alzheimer's disease. Mol. Psychiatry 19, 676–681 (2014).
Henne, W.M., Buchkovich, N.J. & Emr, S.D. The ESCRT pathway. Dev. Cell 21, 77–91 (2011).
Hurley, J.H. & Hanson, P.I. Membrane budding and scission by the ESCRT machinery: it's all in the neck. Nat. Rev. Mol. Cell Biol. 11, 556–566 (2010).
Belly, A. et al. CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines. J. Cell Sci. 123, 2943–2954 (2010).
Ghazi-Noori, S. et al. Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. Brain 135, 819–832 (2012).
Lee, J.A., Beigneux, A., Ahmad, S.T., Young, S.G. & Gao, F.B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561–1567 (2007).
Lee, J.A. & Gao, F.B. Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J. Neurosci. 29, 8506–8511 (2009).
Abe, M. & Bonini, N.M. MicroRNAs and neurodegeneration: role and impact. Trends Cell Biol. 23, 30–36 (2013).
Gascon, E. & Gao, F.B. Cause or effect: misregulation of microRNA pathways in neurodegeneration. Front. Neurosci. 6, 48 (2012).
Gao, F.B. Context-dependent functions of specific microRNAs in neuronal development. Neural Dev. 5, 25 (2010).
Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).
Peça, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011).
Rademakers, R., Neumann, M. & Mackenzie, I.R. Advances in understanding the molecular basis of frontotemporal dementia. Nat. Rev. Neurol. 8, 423–434 (2012).
Seelaar, H., Rohrer, J.D., Pijnenburg, Y.A., Fox, N.C. & van Swieten, J.C. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J. Neurol. Neurosurg. Psychiatry 82, 476–486 (2011).
Bourne, J. & Harris, K.M. Do thin spines learn to be mushroom spines that remember? Curr. Opin. Neurobiol. 17, 381–386 (2007).
Kasai, H., Matsuzaki, M., Noguchi, J., Yasumatsu, N. & Nakahara, H. Structure-stability-function relationships of dendritic spines. Trends Neurosci. 26, 360–368 (2003).
Kasai, H., Fukuda, M., Watanabe, S., Hayashi-Takagi, A. & Noguchi, J. Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci. 33, 121–129 (2010).
Namba, T., Morimoto, K., Sato, K., Yamada, N. & Kuroda, S. Antiepileptogenic and anticonvulsant effects of NBQX, a selective AMPA receptor antagonist, in the rat kindling model of epilepsy. Brain Res. 638, 36–44 (1994).
Lu, W. et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62, 254–268 (2009).
Rozov, A., Sprengel, R. & Seeburg, P.H. GluA2-lacking AMPA receptors in hippocampal CA1 cell synapses: evidence from gene-targeted mice. Front. Mol. Neurosci. 5, 22 (2012).
Cull-Candy, S., Kelly, L. & Farrant, M. Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond. Curr. Opin. Neurobiol. 16, 288–297 (2006).
Liu, S.J. & Zukin, R.S. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci. 30, 126–134 (2007).
Noh, K.M. et al. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Proc. Natl. Acad. Sci. USA 102, 12230–12235 (2005).
Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).
Siegel, G., Saba, R. & Schratt, G. microRNAs in neurons: manifold regulatory roles at the synapse. Curr. Opin. Genet. Dev. 21, 491–497 (2011).
Deo, M., Yu, J.Y., Chung, K.H., Tippens, M. & Turner, D.L. Detection of mammalian microRNA expression by in situ hybridization with RNA oligonucleotides. Dev. Dyn. 235, 2538–2548 (2006).
Almeida, S. et al. Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. Cell Reports 2, 789–798 (2012).
Almeida, S. et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 126, 385–399 (2013).
Chen-Plotkin, A.S. et al. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J. Neurosci. 32, 11213–11227 (2012).
Hébert, S.S., Wang, W.X., Zhu, Q. & Nelson, P.T. A study of small RNAs from cerebral neocortex of pathology-verified Alzheimer's disease, dementia with Lewy bodies, hippocampal sclerosis, frontotemporal lobar dementia, and non-demented human controls. J. Alzheimers Dis. 35, 335–348 (2013).
Chen-Plotkin, A.S. et al. Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum. Mol. Genet. 17, 1349–1362 (2008).
van Swieten, J.C. & Heutink, P. Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol. 7, 965–974 (2008).
Wang, F. et al. Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science 334, 693–697 (2011).
Piguet, O., Hornberger, M., Mioshi, E. & Hodges, J.R. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol. 10, 162–172 (2011).
Filiano, A.J. et al. Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J. Neurosci. 33, 5352–5361 (2013).
Kim, E.J. et al. Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. Cereb. Cortex 22, 251–259 (2012).
Adamczyk, A. et al. GluA3-deficiency in mice is associated with increased social and aggressive behavior and elevated dopamine in striatum. Behav. Brain Res. 229, 265–272 (2012).
Bezprozvanny, I. & Hiesinger, P.R. The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol. Neurodegener. 8, 23 (2013).
Gibbings, D.J., Ciaudo, C., Erhardt, M. & Voinnet, O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 11, 1143–1149 (2009).
Lee, Y.S. et al. Silencing by small RNAs is linked to endosomal trafficking. Nat. Cell Biol. 11, 1150–1156 (2009).
Dutta, R. et al. Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann. Neurol. 73, 637–645 (2013).
Prudencio, M. et al. Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor. Proc. Natl. Acad. Sci. USA 109, 21510–21515 (2012).
Winslow, J.T. Mouse social recognition and preference. Curr. Protoc. Neurosci. 22, 8.16 (2003).
Witt, R.M., Galligan, M.M., Despinoy, J.R. & Segal, R. Olfactory behavioral testing in the adult mouse. J. Vis. Exp. 23, 949 (2009).
Leger, M. et al. Object recognition test in mice. Nat. Protoc. 8, 2531–2537 (2013).
Rodriguez, A., Ehlenberger, D.B., Dickstein, D.L., Hof, P.R. & Wearne, S.L. Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One 3, e1997 (2008).
Mueller, C., Ratner, D., Zhong, L., Esteves-Sena, M. & Gao, G. Production and discovery of novel recombinant adeno-associated viral vectors. Curr. Protoc. Microbiol. 26, 14D.1 (2012).
Chang, K., Elledge, S.J. & Hannon, G.J. Lessons from Nature: microRNA-based shRNA libraries. Nat. Methods 3, 707–714 (2006).
Gao, G.P. & Sena-Esteves, M. Introducing genes into mammalian cells: viral vectors. in Molecular Cloning, Vol 2: A Laboratory Manual (eds. Green, M.R. and Sambrook, J.) 1209–1313 (Cold Spring Harbor Laboratory Press, New York, 2012).
Kutner, R.H., Zhang, X.Y. & Reiser, J. Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nat. Protoc. 4, 495–505 (2009).
Paxinos, G. & Franklin, B.J. Paxinos and Franklin's the Mouse Brain in Stereotaxic Coordinates. 4th edn. (Elsevier Science, San Diego, 2012).
Gascon, E. et al. Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons. J. Neurosci. 30, 12414–12423 (2010).
Gascon, E., Vutskits, L., Jenny, B., Durbec, P. & Kiss, J.Z. PSA-NCAM in postnatally generated immature neurons of the olfactory bulb: a crucial role in regulating p75 expression and cell survival. Development 134, 1181–1190 (2007).
Acknowledgements
We thank S. Ordway and Gao lab members for comments, Y. Li and A. Philbrook for help with some experiments, A. Tapper for sharing behavioral test equipment, the Digital Light Microscopy Core at the University of Massachusetts Medical School (UMMS) for assistance with Golgi staining, the UMMS Viral Vector core for help with AAV vectors, and the University of California–San Francisco Neurodegenerative Disease Brain Bank for some human brain tissues. We also thank R. Rademakers for genotyping some human samples in a previous work51 that we used in the current study and A. Chen-Plotkin for sharing published array data38,40. This work was supported by a UMMS startup fund (F.-B.G.), The Consortium for Frontotemporal Dementia Research (W.W.S.) and the US National Institutes of Health (NS057553, NS066586 and NS079725 to F.-B.G.; DA032283 to W.-D.Y.; MH086509 to S.A.; AG023501 and AG19724 to W.W.S.; and AG016574 to D.W.D. and L.P.).
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E.G., K.L., S.A. and H.Z. performed most experiments. H.R. and W.-D.Y. carried out the electrophysiology analysis and wrote the relevant sections. J.M.V., D.S. and J.J. generated the transgenic mouse lines. L.P., D.W.D. and W.W.S. provided brain tissues from control subjects and subjects with FTD. M.J. and S.A. assisted with behavioral tests. E.G. and F.-B.G. analyzed the data and wrote the manuscript. F.-B.G. conceived and supervised the project.
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Gascon, E., Lynch, K., Ruan, H. et al. Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia. Nat Med 20, 1444–1451 (2014). https://doi.org/10.1038/nm.3717
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DOI: https://doi.org/10.1038/nm.3717
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