Tuning thalamic firing modes via simultaneous modulation of T- and L-type Ca2+ channels controls pain sensory gating in the thalamus.
Two firing modes of thalamocortical (TC) neurons, tonic and burst firings, are thought to reflect the divergent states of sensory signal transmission from the thalamus to the cortex. However, the behavioral consequences of changes in the thalamic firing between the two modes have not been well demonstrated. Moreover, although the firing modes of TC neurons are known to be affected by corticothalamic inputs via thalamic metabotropic glutamate receptor type 1 (mGluR1)-phospholipase C beta4 (PLCbeta4) pathway, its molecular mechanisms have not been well elucidated. We addressed these questions using PLCbeta4-deficient mice, which show decreased visceral pain responses. We demonstrate that burst and tonic firings of TC neurons are concomitantly regulated by PLCbeta4 pathway. Blocking of this pathway by the mutation simultaneously increases bursting and decreases tonic firing of TC neurons through concurrent upregulation of T- and L-type Ca(2+) currents. The mice with increased bursting and decreased tonic firing of TC neurons showed reduced visceral pain responses. Furthermore, we show that modulation of the Ca(2+) channels or protein kinase C (PKC), a downstream molecule of PLCbeta4, altered the firing modes of TC neurons and pain responses in the predicted ways. Our data demonstrate the molecular mechanism and behavioral consequences of altered firing modes of TC neurons in relaying the visceral pain signals. Our study also highlights the thalamic PLCbeta4-PKC pathway as a "molecular switch" for the firing modes of TC neurons and thus for pain sensory gating.
Cheong
Eunji
E
Center for Neural Science, Korea Institute of Science and Technology, Seoul, Korea.
Lee
Sukchan
S
Choi
B Jiwon
BJ
Sun
Minjeong
M
Lee
C Justin
CJ
Shin
Hee-Sup
HS
D000200:Action Potentials / Q000235:genetics*; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D054799:Phospholipase C beta / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D013788:Thalamus / Q000378:metabolism*
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D011493:Protein Kinase C; D054799:Phospholipase C beta