Corticohippocampal Dysfunction In The OBiden Mouse Model Of Primary Oligodendrogliopathy

Sci Rep. 2018 Oct 31;8(1):16116. doi: 10.1038/s41598-018-34414-7.


Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, "how much of the pathobiology of MS can be recapitulated in this model?" The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Axons / pathology
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology*
  • Depression / complications
  • Depression / physiopathology
  • Disease Models, Animal
  • Electroencephalography
  • Endophenotypes
  • Entorhinal Cortex / pathology
  • Entorhinal Cortex / physiopathology
  • Female
  • Gray Matter / pathology
  • Gray Matter / physiopathology
  • Hippocampus / diagnostic imaging
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • KCNQ2 Potassium Channel / metabolism
  • Magnetic Resonance Imaging
  • Male
  • Memory Disorders / complications
  • Memory Disorders / physiopathology
  • Mice
  • Multiple Sclerosis / diagnostic imaging
  • Multiple Sclerosis / pathology*
  • Multiple Sclerosis / physiopathology*
  • Myelin Sheath / pathology
  • Oligodendroglia / pathology*
  • Stress, Physiological
  • Theta Rhythm
  • White Matter / diagnostic imaging
  • White Matter / pathology
  • White Matter / physiopathology


  • KCNQ2 Potassium Channel