title: Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses.
abstract: 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.
authors.forename: Nikita
authors.initials: N
authors.lastname: Rudinskiy
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hawkes
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.forename: Kishore V
authors.initials: KV
authors.lastname: Kuchibhotla
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, MA, USA. bhyman@partners.org.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000386:AIDS-Related Complex / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D010775:Photic Stimulation; D024801:Tauopathies / Q000235:genetics / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics
chemical_list: D008164:Luminescent Proteins; C054369:MAPT protein, human; D016875:tau Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2