TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Sci Rep. 2017 Aug 9;7(1):7711. doi: 10.1038/s41598-017-07394-3.


Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.

Publication types

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

MeSH terms

  • Astrocytes / metabolism
  • Blood-Brain Barrier / metabolism
  • Brain Injuries, Traumatic / etiology
  • Brain Injuries, Traumatic / metabolism
  • Brain Injuries, Traumatic / pathology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Computational Biology / methods
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Gene Expression Profiling
  • Gene Expression*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interneurons / metabolism
  • Losartan / pharmacology
  • Neurons / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I / metabolism
  • Signal Transduction*
  • Transcriptional Activation
  • Transcriptome
  • Transforming Growth Factor beta / metabolism*


  • Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Losartan