Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood-brain barrier

Abstract

The credo that epileptic seizures can be initiated only by "epileptic" neurons has been recently challenged. The recognition of key astrocytic-neuronal communication, and the close interaction and crosstalk between astrocytes and brain endothelial cells, has shifted attention to the blood-brain barrier (BBB) and the "neurovascular unit." Therefore, the pursuit of mechanisms of seizure generation and epileptogenesis now includes investigations of cerebral blood flow and permeability of cerebral microvessels. For example, leukocyte adhesion molecules at the BBB have been proposed to play a role as an initiating factor for pilocarpine-induced status epilepticus, and a viral infection model with a strong BBB etiology has been used to study epileptogenesis. Finally, the fact that in nonepileptic subjects seizures can be triggered by BBB disruption, together with the antiseizure effects obtained by administration of potent antiinflammatory "BBB repair" drugs, has increased the interest in neuroinflammation; both circulating leukocytes and resident microglia have been studied in this context. The dual scope of this review is the following: (1) outline the proposed role of BBB damage and immune cell activation in seizure disorders; and (2) explain how increased cerebrovascular permeability causes neuronal misfiring. The temporal sequence linking seizures to peripheral inflammation and BBB dysfunction remains to be clarified. For example, it is still debated whether seizures cause systemic inflammation or vice versa. The topographic localization of fundamental triggers of epileptic seizures also remains controversial: Are immunologic mechanisms required for seizure generation brain-specific or is systemic activation of immunity sufficient to alter neuronal excitability? Finally, the causative role of "BBB leakage" remains a largely unresolved issue.

Figure 1

Quantitative gradients across the BBB and their predicted effect on neuronal excitability. The size of the molecules and ions depicted on the left side of the figure are roughly proportional to their trans-BBB concentrations. The brain concentration changes indicated by arrows is a semiquantitative means of showing what expected after BBB disruption. The predicted effect on neuronal excitability is also shown. BBB “openings” of different duration and extent and occurring in different regions of the brain may have distinctly different effects.

Figure 2

Predicted changes in synaptic excitability and synaptic changes after BBBD. A glutamatergic synaptic is depicted, but it is likely that all neurotransmitter release mechanisms are similarly affected by depolarization. In these examples the left panel shows normal synaptic transmission where the NMDA receptor is blocked by internal magnesium and synaptic transmission is limited to activation of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors. After cell depolarization neural transmitter release is increased, blockade of NMDA receptors is removed and synaptic hyper-excitability is predicted. Changes in astrocytes (not shown) are perhaps the best documented after disruption of the BBB. Both glutamate uptake and potassium buffering are reduced by yet unknown mechanisms perhaps involving albumin. These, together with the changes shown in the right panel will synergistically increase both neuronal cell excitability and synchronization.