Kv3.1 activation suppresses provoked and spontaneous seizures in a mouse Dravet syndrome model
Sheryl Anne D. Vermudez, Mustafa Q. Hameed, Yongho Choe, Gabrielle E. McGinty, Amanda M. Liebhardt, Rui Lin, Benjamin Hui, Yini Liang, David J. Arce, Henry H. C. Lee, Mustafa Sahin, Alexander RotenbergAbstract
Objective
γ‐Aminobutyric acidergic (GABAergic) parvalbumin‐positive (PV+) interneurons are critical for maintaining cortical inhibitory tone, with their dysfunction predictably leading to epilepsy. Rapid PV+ interneuron firing is essential for their normal function and is maintained in part by potassium voltage‐gated channels. Specifically, the Kv3.1 voltage‐gated potassium channel, which is highly expressed in PV+ interneurons, is essential for maintenance of rapid PV+ interneuron firing. However, whether Kv3.1 expression is modulated by repeated seizures is unknown. Given Kv3.1's role in PV+ cell biology, we tested (1) whether Kv3.1 expression is affected by recurrent seizures and (2) whether Kv3.1‐positive allosteric modulation suppresses either chemoconvulsant seizures or spontaneous seizures in an Scn1a haploinsufficient ( Scn1a +/− ) Dravet syndrome mouse model, which is characterized by PV+ cell dysfunction.
Methods
Seizure threshold was measured in adult wild‐type mice by pentylenetetrazole (PTZ) challenge. In juvenile Scn1a +/− mice, we measured threshold for hyperthermia‐induced seizures, and in adult Scn1a +/− mice spontaneous seizures were recorded by video‐EEG. To test whether seizures alter Kv3.1 expression, cortical tissue was harvested after seizure induction or monitoring for spontaneous seizures, and Kv3.1 protein expression was measured by immunoblot and by immunohistochemistry. As a test of Kv3.1 contribution to seizure control, mice in each group were treated with a tool Kv3.1‐positive allosteric modulator, AUT1.
Results
Kv3.1 protein was reduced in the cortex of mice with either spontaneous or PTZ‐induced seizures. Moreover, Kv3.1 protein was decreased in PV+ interneurons and mislocalized to the cytoplasm rather than the cell membrane in seizing Scn1a +/− mice. Kv3.1 potentiation by AUT1 attenuated three different types of seizures—chemically induced, thermally induced, and spontaneous—in juvenile and adult mice.
Significance
These data highlight the Kv3.1 role as (1) an element of seizure control that declines after recurrent seizures and (2) a potential novel therapeutic target for seizure control in Dravet syndrome and other epilepsies.