Hypermania37 | Dreamstime.comOur understanding of the roles of glia in the nervous system has changed drastically in a relatively short time. Astrocytes are now recognized to be much more than 'space-fillers', and it has been shown that cortical astrocyte processes are organized according to strict rules. New findings from Nedergaard and colleagues reveal that the organization of astrocyte processes is disrupted in models of epilepsy, indicating that these arrangements are likely to be functionally important.
Reactive astrogliosis, in which astrocytes exhibit altered morphology and an upregulation of glial fibrillary acidic protein (GFAP), characterizes many neurological diseases, including epilepsy. The authors investigated whether it is accompanied by alterations in the organization of astrocytic processes. They filled astrocytes in cortical mouse brain slices with lipophilic coloured dyes that become incorporated into the cellular membrane and reveal the fine structure of the cell. Confirming previous studies, comparisons of adjacent astrocytes labelled with two different dyes showed that the processes of each astrocyte occupy a specific 'domain' that shows little overlap with that of neighbouring astrocytes.
Next the authors examined astrocytes in slices taken from mice in which a ferrous chloride solution had been injected into the cortex as a model of traumatic brain-injury-induced epilepsy. Within 1 week of the injury, the domain organization of astrocytes that were classified as 'reactive' owing to their upregulation of the marker GFAP was disrupted. There was a 15-fold increase in the overlap between the space occupied by the processes of adjacent cells, and this increase persisted for up to 6 months after the injury. The loss of domain organization coincided with structural changes in the excitatory neurons that were contacted by the astrocytes, including loss of dendritic spines.
To test whether the disruption in domain organization was a consequence of the injury or a result of injury-induced seizures, the authors suppressed the seizures by treating the mice with valproate. The outcome was a decrease in the degree of domain overlap after injury.
These findings were replicated in a genetic mouse model of epilepsy and in a kainate-induced model of the disease. By contrast, the authors observed no significant change in the degree of domain overlap in a mouse model of Alzheimer's disease, another condition that is associated with reactive astrogliosis. This suggests that the loss of astrocytic domain organization is specific to epilepsy-like conditions.
This study suggests that changes in both astrocytic and neuronal structure and organization might contribute to the abnormality of the circuitry in the epileptic brain. It remains to be determined which of these effects takes place first and how they are related to each other. Because the structural changes associated with febrile seizures in early childhood have been linked to an increased risk for developing epilepsy in adulthood, it might be important to prevent these morphological changes occurring.