Media Releases

University of Toronto biologists pave the way for improved epilepsy treatments

June 5, 2014

Discovery may lead to relief for victims of a range of neurological disorders

TORONTO, ON – Uni­ver­si­ty of Toron­to biol­o­gists lead­ing an inves­ti­ga­tion into the cells that reg­u­late prop­er brain func­tion, have iden­ti­fied and locat­ed the key play­ers whose actions con­tribute to afflic­tions such as epilep­sy and schiz­o­phre­nia. The dis­cov­ery is a major step toward devel­op­ing improved treat­ments for these and oth­er neu­ro­log­i­cal dis­or­ders.

“Neu­rons in the brain com­mu­ni­cate with oth­er neu­rons through synaps­es, com­mu­ni­ca­tion that can either excite or inhib­it oth­er neu­rons,” said Pro­fes­sor Melanie Wood­in in the Depart­ment of Cell and Sys­tems Biol­o­gy at the Uni­ver­si­ty of Toron­to (U of T), lead inves­ti­ga­tor of a study pub­lished today in Cell Reports. “An imbal­ance among the lev­els of exci­ta­tion and inhi­bi­tion – a tip towards exci­ta­tion, for exam­ple – caus­es improp­er brain func­tion and can pro­duce seizures. We iden­ti­fied a key com­plex of pro­teins that can reg­u­late exci­ta­tion-inhi­bi­tion bal­ance at the cel­lu­lar lev­el.”

This com­plex brings togeth­er three key pro­teins – KCC2, Neto2 and GluK2 – required for inhibito­ry and exci­ta­to­ry synap­tic com­mu­ni­ca­tion. KCC2 is required for inhibito­ry impuls­es, GluK2 is a recep­tor for the main exci­ta­to­ry trans­mit­ter glu­ta­mate, and Neto2 is an aux­il­iary pro­tein that inter­acts with both KCC2 and GluK2.  The dis­cov­ery of the com­plex of three pro­teins is path­break­ing as it was pre­vi­ous­ly believed that KCC2 and GluK2 were in sep­a­rate com­part­ments of the cell and act­ed inde­pen­dent­ly of each oth­er.

“Find­ing that they are all direct­ly inter­act­ing and can co-reg­u­late each other’s func­tion reveals for the first time a sys­tem that can medi­ate exci­ta­tion-inhi­bi­tion bal­ance among neu­rons them­selves,” said Vivek Mahade­van, a PhD can­di­date in Woodin’s group and lead author of the study.

Mahade­van and fel­low researchers made the dis­cov­ery via bio­chem­istry, flu­o­res­cence imag­ing and elec­tro­phys­i­ol­o­gy exper­i­ments on mice brains. The most fruit­ful tech­nique was the appli­ca­tion of an advanced sen­si­tive gel sys­tem to deter­mine native pro­tein com­plex­es in neu­rons, called Blue Native PAGE. The process pro­vid­ed the bio­chem­i­cal con­di­tions nec­es­sary to pre­serve the pro­tein com­plex­es that nor­mal­ly exist in neu­rons. Blue Native PAGE is advan­ta­geous over stan­dard gel elec­trophore­sis, where pro­teins are sep­a­rat­ed from their nor­mal pro­tein com­plex­es based on their mol­e­c­u­lar weights.

“The results reveal the pro­teins that can be tar­get­ed by drug man­u­fac­tur­ers in order to reset imbal­ances that occur in neu­ro­log­i­cal dis­or­ders such as epilep­sy, autism spec­trum dis­or­der, schiz­o­phre­nia and neu­ro­path­ic pain,” said Wood­in. “There is no cure for epilep­sy; the best avail­able treat­ments only con­trol its effects, such as con­vul­sions and seizures. We can now imag­ine pre­vent­ing them from occur­ring in the first place.”

“It was the cel­lu­lar mech­a­nisms that deter­mine the exci­ta­tion-inhi­bi­tion bal­ance that need­ed to be iden­ti­fied. Now that we know the key role played by KCC2 in mod­er­at­ing exci­ta­to­ry activ­i­ty, fur­ther research can be done into its occa­sion­al dys­func­tion and how it can also be reg­u­lat­ed by exci­ta­to­ry impuls­es,” said Mahade­van.

Oth­er inves­ti­ga­tors involved in the research includ­ed sci­en­tists at the Hos­pi­tal for Sick Chil­dren Research Insti­tute, Van­der­bilt Uni­ver­si­ty School of Med­i­cine, Jew­ish Gen­er­al Hos­pi­tal at McGill Uni­ver­si­ty, and the Insti­tute of Bio­med­i­cine, Anato­my at the Uni­ver­si­ty of Helsin­ki. The find­ings are report­ed in the arti­cle “Kainate Recep­tors Coex­ist in a Func­tion­al Com­plex with KCC2 and Reg­u­late Chlo­ride Home­osta­sis in Hip­pocam­pal Neu­rons” pub­lished online June 5 in Cell Reports. The research was sup­port­ed by fund­ing from the Cana­di­an Insti­tutes of Health Research, the Nation­al Insti­tutes of Health, and the Acad­e­my of Fin­land.

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Melanie Wood­in
Depart­ment of Cell and Sys­tems Biol­o­gy
Uni­ver­si­ty of Toron­to

Vivek Maha­da­van
Depart­ment of Cell and Sys­tems Biol­o­gy
Uni­ver­si­ty of Toron­to

Sean Bet­tam
Com­mu­ni­ca­tions, Fac­ul­ty of Arts & Sci­ence
Uni­ver­si­ty of Toron­to