title: Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy.
abstract: The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia.
  
  
  CONCLUSIONS
  The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Clair A
authors.identifier: http://orcid.org/0000-0003-1190-4462
authors.initials: CA
authors.lastname: Booth
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, Exeter EX4 4PS, United Kingdom.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-8236-9033
authors.initials: T
authors.lastname: Ridler
authors.affiliation: Lilly UK, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Tracey K
authors.initials: TK
authors.lastname: Murray
authors.affiliation: Lilly UK, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ward
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, Exeter EX4 4PS, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: de Groot
authors.affiliation: College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4SB, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Goodfellow
authors.affiliation: Lilly UK, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Keith G
authors.identifier: http://orcid.org/0000-0002-4678-3886
authors.initials: KG
authors.lastname: Phillips
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, Exeter EX4 4PS, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, 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: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001703:Biophysics; D004195:Disease Models, Animal; D004558:Electric Stimulation; D018728:Entorhinal Cortex / Q000473:pathology*; D005071:Evoked Potentials / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024801:Tauopathies / Q000235:genetics / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D010320:Parvalbumins; D016875:tau Proteins
keywords: Tau; dementia; gamma oscillations; grid cells; medial entorhinal cortex