Fibrotic scar model and TGF‐β1 differently modulate action potential firing and voltage‐dependent ion currents in hippocampal neurons in primary culture

Abstract

Traumatic injury of the central nervous system is accompanied by various functional and morphological changes. Animal models of traumatic brain injury are commonly used to investigate changes in behaviour, morphology, in the expression of various proteins around the site of the injury, or the expression of diagnostically important biomarkers. Excitability of a single neuron at, or close to, the site of injury was rarely investigated. Several in vitro models were developed which allow such investigation. In the present work, we employed a fibrotic scar model according to Kimura-Kuroda and coauthors to analyse altered excitability of rat hippocampal neurons under the conditions mimicking traumatic brain injury. Hippocampal neurons from newborn rats were cultured either on a fibrotic scar model or in the presence of TGF-β1, a cytokine secreted at a brain injury site that may have both neuroprotective and neurodegenerative function. Fibrotic scar facilitated ability of neonatal hippocampal neurons to fire action potential series by increasing the density of voltage activated sodium and potassium currents. Chondroitin sulphate proteoglycans played substantial role in these effects, as proven by their full reversion after administration of Chondroitinase ABC. In contrast, TGF-β1 did not contribute to them. An application of TGF-β1 itself attenuated generation of action potentials, inhibited sodium current and potentiated potassium currents. Main alteration of electrophysiological parameters of neonatal hippocampal neurons caused by a fibrotic scar model is enhanced excitability. TGF-β1 may have predominantly neuroprotective role in injured rat hippocampus.

The Role of Neuroinflammatory Mediators in the Pathogenesis of Traumatic Brain Injury: A Narrative Review

“…The increased sodium current as a result of fibrotic scar formation may contribute to the epileptogenesis process post TBI. 90 Disruption of the BBB integrity may cause an increase in albumin levels in the extracellular space (ECS), 91,92 which may bind to TGFβRI and TGFβRII receptors, thereby activating the TGF-β signaling pathway (SMAD). 93 This pathway has been shown to be associated with post-translational changes in voltage-dependent ion channels, thus leading to changes in neuronal excitability (seizures).…”

“…The modulatory effects of TGF-β and fibrotic scar tissue should be further investigated in future TBI studies. The increased sodium current as a result of fibrotic scar formation may contribute to the epileptogenesis process post TBI . Disruption of the BBB integrity may cause an increase in albumin levels in the extracellular space (ECS), , which may bind to TGFβRI and TGFβRII receptors, thereby activating the TGF-β signaling pathway (SMAD) .…”