title: Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons.
abstract: 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/alpha1A subunit), lethargic (lh; beta4 subunit), and stargazer (stg; gamma2 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/alpha1G, Cav3.2/alpha1H, or Cav3.3/alpha1I, 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.
authors.affiliation: Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mayra
authors.initials: M
authors.lastname: Mori
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Burgess
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000209:etiology / Q000378:metabolism*; D015870:Gene Expression; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D012333:RNA, Messenger / Q000378:metabolism; D013788:Thalamus / Q000166:cytology / Q000378:metabolism*
chemical_list: D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D021122:Protein Subunits; D012333:RNA, Messenger