Optogenetic activation of VGLUT2-expressing excitatory neurons blocks epileptic seizure-like activity in the mouse entorhinal cortex.

Abstract

We investigated whether an anti-epileptic effect is obtained by selectively activating excitatory neurons expressing ChR2 under the promoter for the synaptic vesicular glutamate transporter 2 (VGLUT2). VGLUT2-expressing cells were optically stimulated while local field potential and whole-cell patch-clamp recordings were performed in mouse entorhinal cortical slices perfused with the proconvulsive compound 4-aminopyridine (4-AP). In control conditions, blue light flashes directly depolarized the majority of putative glutamatergic cells, which in turn synaptically excited GABAergic interneurons. During bath perfusion with 4-AP, photostimuli triggered a fast EPSP-IPSP sequence which was often followed by tonic-clonic seizure-like activity closely resembling spontaneous ictal discharges. The GABAA-receptor antagonist gabazine blocked the progression of both light-induced and spontaneous seizures. Surprisingly, prolonged photostimuli delivered during ongoing seizures caused a robust interruption of synchronous discharges. Such break was correlated with a membrane potential depolarization block in principal cells, while putative GABAergic interneurons changed their firing activity from a burst-like to an irregular single-spike pattern. These data suggest that photostimulation of glutamatergic neurons triggers seizure-like activity only in the presence of an intact GABAergic transmission and that selectively activating the same glutamatergic cells robustly interrupts ongoing seizures by inducing a strong depolarization block, resulting in the disruption of paroxysmal burst-like firing.

• Authors: Latefa Yekhlef, Gian Luca Breschi, Stefano Taverna
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 43230 (02 23 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28230208 (Publication Type: Journal Article)

Chemical References

• Slc17a6 protein, mouse
• Vesicular Glutamate Transport Protein 2

Topics

• Action Potentials
• Animals
• Entorhinal Cortex (pathology)
• Mice
• Neurons (metabolism, physiology)
• Optogenetics
• Patch-Clamp Techniques
• Seizures (physiopathology)
• Vesicular Glutamate Transport Protein 2