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.

Hippocampal sharp wave-ripple complexes (SPW-Rs) occur during slow-wave sleep and behavioral immobility and are thought to represent stored information that is transferred to the neocortex during memory consolidation. Here we show that stimuli that induce long-term potentiation (LTP), a neurophysiological correlate of learning and memory, can lead to the generation of SPW-Rs in rat hippocampal slices. The induced SPW-Rs have properties that are identical to spontaneously generated SPW-Rs: they originate in CA3, propagate to CA1 and subiculum and require AMPA/kainate receptors. Their induction is dependent on NMDA receptors and involves changes in interactions between clusters of neurons in the CA3 network. Their expression is blocked by low-frequency stimulation but not by NMDA receptor antagonists. These data indicate that induction of LTP in the recurrent CA3 network may facilitate the generation of SPW-Rs.

Pathophysiology of the neurovascular unit (NVU) is commonly seen in neurological diseases. The typical features of NVU pathophysiology include tissue hypoxia, inflammatory and angiogenic activation, as well as initiation of complex molecular interactions between cellular (brain endothelial cells, astroctyes, pericytes, inflammatory cells, and neurons) and acellular (basal lamina) components of the NVU, jointly resulting in increased blood-brain barrier permeability, brain edema, neurovascular uncoupling, and neuronal dysfunction and damage. The evidence of important role of the brain vascular compartment in disease pathogenesis has elicited the debate whether the primary vascular events may be a cause of the neurological disease, as opposed to a mere participant recruited by a primary neuronal origin of pathology? Whereas some hereditary and acquired cerebral angiopathies could be considered a primary cause of neurological symptoms of the disease, the epidemiological studies showing a high degree of comorbidity among vascular disease and dementias, including Alzheimer's disease, as well as migraine and epilepsy, suggested that primary vascular pathology may be etiological factor causing neuronal dysfunction or degeneration in these diseases. This review focuses on recent hypotheses and evidence, suggesting that pathophysiology of the NVU may be initiating trigger for neuronal pathology and subsequent neurological manifestations of the disease.