TGF\u03b2 signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Soo Young Kim,Oscar Vazquez,Christapher S Morrissey,Kristina Lippmann,Isabel Parada,Albert J Becker,Alon Friedman,Feng Gu,Dan Z Milikovsky,Vladimir V Senatorov,David A Prince,Daniela Kaufer,Uwe Heinemann

doi:10.1038/s41598-017-07394-3

Abstract

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.

Highlights

Brain damage due to stroke or brain trauma often yields neuronal hypersynchrony, potentially resulting in epilepsy and ensuing cognitive morbidities[1, 2]
We have further shown that exposure of the typically-secluded brain environment to albumin, the most abundant blood protein, is sufficient to induce epileptiform activity and recurring seizures, and this depends on activation of TGFβ signaling[4,5,6,7]
Consistent with previous findings of albumin extravasation in rodent[6] and human[14] epileptic brains, albumin was co-localized within cells expressing glial fibrillary acidic protein (GFAP), a marker for astrocytes, in the undercut cortex (Fig. 1c)

Summary

Introduction

Brain damage due to stroke or brain trauma often yields neuronal hypersynchrony, potentially resulting in epilepsy and ensuing cognitive morbidities[1, 2]. We performed comparative analyses using human hippocampal samples as well as five different rat models of neurological insults in search of shared mechanisms These include partial cortical isolation (“undercut”) as a model of traumatic brain injury[9, 10], photothrombosis as a model of ischemic stroke[11, 12], chemically-induced focal BBB disruption[4, 5], direct brain exposure to serum albumin[4] or TGFβ17, and chronic pharmaco-resistant temporal lobe epilepsy in human patients. Our findings suggest that albumin-activated TGFβ signaling alters the microenvironment around inhibitory interneurons, as a potential mechanism underlying delayed deficits in neural inhibition following different injuries to the brain

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Results

Conclusion