TGF-  receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis

Abstract

It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5-49 days after treatment, but only 14% (n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor beta receptors (TGF-betaRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-d-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-betaR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% (n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-betaRs as a possible therapeutic target.

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

“…The angiogenic response associated with dyskinesia may thus represent an adaptation to locally increased metabolic demands caused by altered patterns of neuronal activity. Similar to the situation reported in other neurological conditions (Ivens et al, 2007;van Vliet et al, 2007), angiogenesis and altered BBB permeability may, however, itself contribute to the abnormal neuronal activities and (in the case of PD) it may also alter the kinetics of L-DOPA entry into the brain. In support of this contention, the development of L-DOPA-induced AIMs can be delayed by corticosterone co-treatment (Barnum et al, 2008), which is known to inhibit brain angiogenesis (Ekstrand et al, 2008b) and to stabilize the BBB.…”

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

“…Extravasation of serum albumin into the brain after SE appears to promote the progression of epilepsy, as direct administration of albumin into the brain promotes inflammation and can result in development of spontaneous seizures (65). Moreover, degradation of the BBB has been demonstrated in humans after seizures by measuring the extravasation of serum albumin into the brain parenchyma (2).…”

Astrocytes and Epilepsy

“…62 Albumin released into the brain through vascular permeability is reported in animal studies to be taken up by astrocytes through transforming growth factor-b receptors (TGF-bR), and the transcriptional activation of downstream pathways 63 resulting in the down regulation of inward rectifying potassium (Kir 4.1) channels in astrocytes, astrocytic activation, increased inflammation, and reduced inhibitory transmission. 64 Several changes in molecular expression have been reported in the blood-brain barrier, the astrocyte endothelial cell interface. The erythropoietin receptor (EPO-r) is strongly expressed on the capillaries of the sclerotic hippocampus, 60 particularly in regions of extensive neuronal loss and gliosis (CA3, CA1, and dentate hilus).…”