title: Trajectory of Parvalbumin Cell Impairment and Loss of Cortical Inhibition in Traumatic Brain Injury.
abstract: Many neuropsychiatric symptoms that follow traumatic brain injury (TBI), including mood disorders, sleep disturbance, chronic pain, and posttraumatic epilepsy (PTE) are attributable to compromised cortical inhibition. However, the temporal trajectory of cortical inhibition loss and its underlying mechanisms are not known. Using paired-pulse transcranial magnetic stimulation (ppTMS) and immunohistochemistry, we tracked functional and cellular changes of cortical inhibitory network elements after fluid-percussion injury (FPI) in rats. ppTMS revealed a progressive loss of cortical inhibition as early as 2 weeks after FPI. This profile paralleled the increasing levels of cortical oxidative stress, which was accompanied by a gradual loss of parvalbumin (PV) immunoreactivity in perilesional cortex. Preceding the PV loss, we identified a degradation of the perineuronal net (PNN)-a specialized extracellular structure enwrapping cortical PV-positive (PV+) inhibitory interneurons which binds the PV+ cell maintenance factor, Otx2. The trajectory of these impairments underlies the reduced inhibitory tone, which can contribute to posttraumatic neurological conditions, such as PTE. Taken together, our results highlight the use of ppTMS as a biomarker to track the course of cortical inhibitory dysfunction post-TBI. Moreover, the neuroprotective role of PNNs on PV+ cell function suggests antioxidant treatment or Otx2 enhancement as a promising prophylaxis for post-TBI symptoms.
authors.affiliation: Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.|Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan.
authors.forename: Tsung-Hsun
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Henry Hing Cheong
authors.initials: HHC
authors.lastname: Lee
authors.affiliation: Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mustafa Qadir
authors.initials: MQ
authors.lastname: Hameed
authors.affiliation: Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual-Leone
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, MA 02138, USA.
authors.forename: Takao K
authors.initials: TK
authors.lastname: Hensch
authors.affiliation: Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rotenberg
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000473:pathology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D007839:Functional Laterality; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D051857:Otx Transcription Factors / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D020318:Rats, Long-Evans; D050781:Transcranial Magnetic Stimulation
chemical_list: D051857:Otx Transcription Factors; C000609576:Otx2 protein, rat; D010320:Parvalbumins
keywords: Otx2; intracortical inhibition; oxidative stress; perineuronal nets; transcranial magnetic stimulation