Deletion of phospholipase C beta4 in thalamocortical relay nucleus leads to absence seizures.
Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca(2+) currents. We recently demonstrated that the phospholipase C beta4 (PLCbeta4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T- and L-type Ca(2+) currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLCbeta4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLCbeta4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLCbeta4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca(2+) channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLCbeta4-deficient mice as a potential animal model for absence seizures.
Cheong
Eunji
E
Center for Neural Science, Korea Institute of Science and Technology, Seoul 136-791, Korea.
Zheng
Yihong
Y
Lee
Kyoobin
K
Lee
Jungryun
J
Kim
Seongwook
S
Sanati
Maryam
M
Lee
Sukyung
S
Kim
Yeon-Soo
YS
Shin
Hee-Sup
HS
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects; D004569:Electroencephalography; D020536:Enzyme Activators / Q000494:pharmacology; D004832:Epilepsy, Absence / Q000201:enzymology* / Q000503:physiopathology; D018755:GABA Agonists / Q000494:pharmacology; D020868:Gene Silencing; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D054799:Phospholipase C beta / Q000235:genetics / Q000502:physiology*; D013788:Thalamus / Q000201:enzymology / Q000503:physiopathology*
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020536:Enzyme Activators; D018755:GABA Agonists; D054799:Phospholipase C beta; C518043:Plcb4 protein, mouse