Abstract
Epilepsy is a group of neurological disorders commonly associated with the neuronal malfunction leading to generation of seizures. Recent reports point to a possible contribution of astrocytes into this pathology. We used the lithium-pilocarpine model of status epilepticus (SE) in rats to monitor changes in astrocytes. Experiments were performed in acute hippocampal slices 2–4 weeks after SE induction. Nissl staining revealed significant neurodegeneration in the pyramidal cell layers of hippocampal CA1, CA3 areas, and the hilus, but not in the granular cell layer of the dentate gyrus. A significant increase in the density of astrocytes stained with an astrocyte-specific marker, sulforhodamine 101, was observed in CA1 stratum (str.) radiatum. Astrocytes in this area were also whole-cell loaded with a morphological tracer, Alexa Fluor 594, for two-photon excitation imaging. Sholl analyses showed no changes in the size of the astrocytic domain or in the number of primary astrocytic branches, but a significant reduction in the number of distal branches that are resolved with diffraction-limited light microscopy (and are thought to contain Ca2+ stores, such as mitochondria and endoplasmic reticulum). The atrophy of astrocytic branches correlated with the reduced size, but not overall frequency of Ca2+ events. The volume tissue fraction of nanoscopic (beyond the diffraction limit) astrocytic leaflets showed no difference between control and SE animals. The results of spatial entropy-complexity spectrum analysis were also consistent with changes in ratio of astrocytic branches vs. leaflets. In addition, we observed uncoupling of astrocytes through the gap-junctions, which was suggested as a mechanism for reduced K+ buffering. However, no significant difference in time-course of synaptically induced K+ currents in patch-clamped astrocytes argued against possible alterations in K+ clearance by astrocytes. The magnitude of long-term-potentiation (LTP) was reduced after SE. Exogenous D-serine, a co-agonist of NMDA receptors, has rescued the initial phase of LTP. This suggests that the reduced Ca2+-dependent release of D-serine by astrocytes impairs initiation of synaptic plasticity. However, it does not explain the failure of LTP maintenance which may be responsible for cognitive decline associated with epilepsy.
Highlights
Epilepsy is a group of neurological disorders, associated with pathological synchronization of neuronal activity causing seizures
There was no significant difference in the number of primary branches, the peak number of the branches and size of the astrocytic domain in control and SE animals (Supplementary Figure 3)
The number of distal branches was significantly lower after SE (control, n = 6; SE, n = 6; two-way repeated measures (RM) ANOVA, F(1,5) = 6.862, p = 0.047, partial η2 = 0.578, with a mean difference of 5.61 ± 2.14; Figure 2B)
Summary
Epilepsy is a group of neurological disorders, associated with pathological synchronization of neuronal activity causing seizures. Pathological synchronization of excitatory neurons may result from enhanced inhibition of a relatively small group of inhibitory interneurons, which synchronously disinhibits numerous excitatory neurons. This is called “rebound” excitation and may make all these cells to fire in synchrony (Paz and Huguenard, 2015). The K+ hypothesis of epilepsy suggests that extracellular accumulation of this ion in the brain depolarizes neurons and cause epileptiform activity (Green, 1964; Fertziger and Ranck, 1970; Fröhlich et al, 2008). It has long been reported that periodic elevations of extracellular K+ concentration could produce longterm changes in neuronal excitability, making the network prone to epileptogenesis (Semyanov and Godukhin, 1997)
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