title: Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.
abstract: The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function.
  
  
  CONCLUSIONS
  Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Clair A
authors.identifier: http://orcid.org/0000-0003-1190-4462
authors.initials: CA
authors.lastname: Booth
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0001-9411-4022
authors.initials: J
authors.lastname: Witton
authors.affiliation: Department of Engineering Mathematics, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Jakub
authors.initials: J
authors.lastname: Nowacki
authors.affiliation: Department of Engineering Mathematics, University of Bristol, Bristol BS8 1TD, United Kingdom, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, United Kingdom, and.
authors.forename: Krasimira
authors.identifier: http://orcid.org/0000-0002-6294-7051
authors.initials: K
authors.lastname: Tsaneva-Atanasova
authors.affiliation: School of Physiology and Pharmacology and.
authors.forename: Matthew W
authors.identifier: http://orcid.org/0000-0001-5396-3108
authors.initials: MW
authors.lastname: Jones
authors.affiliation: School of Physiology and Pharmacology and Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter EX4 4PS, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
authors.affiliation: School of Physiology and Pharmacology and Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, University of Exeter, Exeter EX4 4PS, United Kingdom J.T.Brown@exeter.ac.uk.
authors.forename: Jonathan T
authors.identifier: http://orcid.org/0000-0001-5269-7661
authors.initials: JT
authors.lastname: Brown
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000235:genetics / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D005583:Fourier Analysis; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009415:Nerve Net / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology*; D013559:Symbiosis / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D024801:Tauopathies / Q000150:complications / Q000235:genetics / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016875:tau Proteins
keywords: GABA; intrinsic properties; place cell; resonance; synaptic plasticity