Seizures induce c-fos expression in a subset of astrocytes, termed fostrocytes, that dampen subsequent seizures
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Objective
The original goal was to map neuronal circuits activated by spontaneous seizures in models of temporal lobe epilepsy. Studies used the c-fos driven TRAP2 system, which has been used successfully to label neurons after seizures. Unexpectedly, astrocytes were also labeled, then shown to express c-fos in a sustained manner after seizures. The role of these so-called fostrocytes in spontaneous seizures was studied using novel Cre-dependent AAVs.
Methods
Studies used a homozygous mouse line produced by crossing TRAP2 Cre-driver mice with the Ai9 Cre-reporter line. Seizures were induced using electrical stimulation, kainic acid, or pilocarpine. Cre-dependent AAVs used the GFAP promoter to drive expression of either the catalytic A chain of diphtheria toxin (DTA), GFP, or empty vector. Spontaneous seizures were continuously recorded using EEG.
Results
Discrete seizures in naïve mice evoked transient c-fos expression in all astrocytes, while status epilepticus evoked a higher and sustained level of c-fos expression. Timing the activation of the TRAP2 system allowed specific labeling of the subset of astrocytes with high c-fos expression. These cells were colocalized with established astrocyte markers, showed reactive astrocyte morphology, and were selectively labeled by GFAP-driven Cre-dependent AAVs. Ablation of fostrocytes in spontaneously seizing mice increased seizure frequency.
Significance
Next-generation sequencing studies have revealed a great diversity of astrocyte subtypes, identifying clusters with up-regulated c-fos expression in patients with neurological disorders. In conclusion, these studies suggest that therapies that augment the activity of c-fos expressing astrocytes would have anti-seizure activity.
Key points:
➢ Discrete seizures triggered a transient expression of c-fos in all astrocytes, while status epilepticus triggered its prolonged expression in a subset of astrocytes.
➢ The TRAP2 system expresses inducible Cre recombinase controlled by the Fos gene, providing genetic access to astrocytes that express c-fos at high levels.
➢ Cre-dependent delivery of a diphtheria toxin selectively ablated these fostrocytes and exacerbated spontaneous seizures.
➢ Novel therapies that augment the activity of fostrocytes are predicted to reduce seizure burden.
