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The Journal of Neuroscience, August 1, 2002, 22(15):6362-6371
Mutations in High-Voltage-Activated Calcium Channel Genes
Stimulate Low-Voltage-Activated Currents in Mouse Thalamic Relay
Neurons
Yi
Zhang,
Mayra
Mori,
Daniel L.
Burgess, and
Jeffrey L.
Noebels
Developmental Neurogenetics Laboratory, Department of Neurology,
Baylor College of Medicine, Houston, Texas 77030
Ca2+ currents, especially those activated at low
voltages (LVA), influence burst generation in thalamocortical circuitry
and enhance the abnormal rhythmicity associated with absence epilepsy. Mutations in several genes for high-voltage-activated (HVA)
Ca2+ channel subunits are linked to spike-wave
seizure phenotypes in mice; however, none of these mutations are
predicted to increase intrinsic membrane excitability or directly
enhance LVA currents. We examined biophysical properties of both LVA
and HVA Ca2+ currents in thalamic cells of
tottering (tg; CaV2.1/ 1A
subunit), lethargic (lh;  4
subunit), and stargazer (stg;  2
subunit) brain slices. We observed 46, 51, and 45% increases in peak
current densities of LVA Ca2+ currents evoked at
 50 mV from 110 mV in tg, lh, and
stg mice, respectively, compared with wild type. The
half-maximal voltages for steady-state inactivation of LVA currents
were shifted in a depolarized direction by 7.5-13.5 mV in all three
mutants, although no alterations in the time-constant for recovery from
inactivation of LVA currents were found. HVA peak current densities in
tg and stg were increased by 22 and 45%,
respectively, and a 5 mV depolarizing shift of the activation curve was
observed in lh. Despite elevated LVA amplitudes, no
alterations in mRNA expression of the genes mediating T-type subunits,
CaV3.1/1G, CaV3.2/1H, or
CaV3.3/1I, were detected in the three mutants. Our data
demonstrate that mutation of CaV2.1 or regulatory subunit
genes increases intrinsic membrane excitability in thalamic neurons by
potentiating LVA Ca2+ currents. These alterations
increase the probability for abnormal thalamocortical synchronization
and absence epilepsy in tg, lh, and
stg mice.
Key words:
Ca2+ currents; thalamocortical relay
cells; absence seizures; stargazer; tottering; lethargic; calcium ion
channel mutation
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156362-10$05.00/0
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