Kv3.1 activation suppresses provoked and spontaneous seizures in a mouse Dravet syndrome model.
TL;DR
The Kv3.1 role is highlighted as an element of seizure control that declines after recurrent seizures and a potential novel therapeutic target for seizure control in Dravet syndrome and other epilepsies.
Abstract
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.