Astrocytes in the epileptic brain

Abstract

The roles that astrocytes play in the evolution of abnormal network excitability in chronic neurological disorders involving brain injury, such as acquired epilepsy, are receiving renewed attention due to improved understanding of the molecular events underpinning the physiological functions of astrocytes. In epileptic tissue, evidence is pointing to enhanced chemical signaling and disrupted linkage between water and potassium balance by reactive astrocytes, which together conspire to enhance local synchrony in hippocampal microcircuits. Reactive astrocytes in epileptic tissue both promote and oppose seizure development through a variety of specific mechanisms; the new findings suggest several novel astrocyte-related targets for drug development.

Figure 1. Integrated Control of Synaptic Release Probability by Astrocytes in Dentate Molecular Layer

Immunoelectron microscopy suggests the existence of NR2B-containing NMDA receptors on perforant path terminals opposing astrocytic membranes that contain vesicles close to the astrocytic plasma membrane (Jourdain et al., 2007). Cell-derived ATP and glutamate act on two astrocytic Gq-coupled GPCRs, mGluR5 and P2Y1R, to increase [Ca²⁺]i and promote astrocytic release of glutamate into the extrasynaptic space. The resulting activation of presynaptic NMDA receptors appears to contribute to frequency facilitation at perforant path synapses.

Figure 2. Hypothesis for Role of Astrocytes in Water Balance Dysfunction in Epilepsy

The left panel depicts a typical bipolar brain astrocyte with processes in the neuropil (bottom) and endfeet near the perivascular space (top). The distribution of aquaporin 4 water channels (red) and Kir4.1 potassium channels (blue) is shown. Following neuronal activity, the potassium taken up into astrocytes via Kir4.1 is accompanied by water entry through AQP4 to maintain osmotic balance. Excess water may be dumped into the perivascular space by AQP4. In the epileptic state (right panel), there is a partial redistribution of AQP4 away from perivascular endfeet to the neuropil. The predicted consequences of this redistribution include enhanced entry of water into the neuropil but impaired egress of water into perivascular space, leading to astrocytic swelling and reduced interstitial space volume and thus enhanced ephaptic interactions among neurons.

Figure 3. Hypothesis for Enhanced Ability of Reactive Astrocytes to Release Glutamate

(Left) Scheme for control of astrocytic glutamate release by two G protein-coupled receptors. (Right) In the epileptic brain, mGluR5 is upregulated, and activated microglia as well as reactive astrocytes release TNFα, which acts on TNFR1 receptors in a pathway that promotes prostaglandin formation. Prostaglandin in turn activates a Gq-coupled prostanoid receptor that boosts intra-astrocyte Ca²⁺ release and thus astrocytic glutamate release. Hypothesis adapted from work reported by Bezzi et al. (1998, 2001) and Domercq et al. (2006).