Abstract
Objective
Development of novel therapies for temporal lobe epilepsy is hindered by a lack of models suitable for drug screening. While testing the hypothesis that “inhibiting inhibitory neurons” was sufficient to induce seizures, it was discovered that a mild electrical kindling protocol of VGAT‐Cre mice led to spontaneous motor and electrographic seizures. This study characterizes these seizures and investigates the mechanism.
Methods
Mice were implanted with electroencephalographic (EEG) headsets that included a stimulating electrode in the hippocampus before being electrically kindled. Seizures were evaluated by review of EEG recordings and behavior. γ‐Aminobutyric acidergic (GABAergic) neurotransmission was evaluated by quantitative polymerase chain reaction, immunocytochemistry, Western blot, and electrophysiology.
Results
Electrical kindling of VGAT‐Cre mice induces spontaneous recurring seizures after a short latency (6 days). Seizures occur 1‐2 times per day in both male and female mice, with only minimal neuronal death. These mice express Cre recombinase under the control of the vesicular GABA transporter (VGAT), a gene that is specifically expressed in GABAergic inhibitory neurons. The insertion of Cre disrupts the expression of VGAT mRNA and protein, and impairs GABAergic synaptic transmission in the hippocampus.
Significance
Kindled VGAT‐Cre mice can be used to study the mechanisms involved in epileptogenesis and may be useful for screening novel therapeutics.
SEP