Reduced gamma-aminobutyric acid (GABA) inhibition has been implicated in both anxiety and epilepsy.GAD65-/- (NOD/LtJ) mice have significantly decreased basal GABA levels in the brain and a lowered threshold for seizure generation.One fifth of GAD65 -/- mice experienced stress-induced seizures weekend friend juneshine upon exposure to an open field at 4 weeks of age.In each successive week until 8 weeks of age, the latency to seizures decreased with prior seizure experience.100% of GAD65-/- mice exhibited stress-induced seizures by the end of 8 weeks.
GAD65-/- mice also exhibited marked impairment in open field exploratory behavior and deficits in spatial learning acquisition on a Barnes maze.Anxiety-like behavior in an open field was observed prior to seizure onset and was predictive of subsequent seizures.Immunohistochemical characterization of interneuron subtypes in GAD65-/- mice showed a selective decrease in GABA and neuropeptide Y (NPY) levels and no change in calbindin (CLB) or calretinin (CLR) immunoreactivity in the hippocampus.Stem cells from the medial ganglionic eminence (MGE) were injected into the hippocampal hilus to restore 3 nef runes GABAergic interneurons.One week after transplantation, MGE-transplanted mice demonstrated significant seizure resistance compared to sham surgical controls.
The percent area of GFP+ MGE graft in the hippocampus correlated significantly with the increase in seizure latency.Our data indicate that impaired GABAergic neurotransmission can cause anxiety-like behavior and stress-induced seizures that can be rescued by MGE stem cell transplantation.