The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression.
The mouse mutant ducky and its allele ducky(2J) represent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the alpha2delta-2 calcium channel subunit. Of relevance to the ataxic phenotype, alpha2delta-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2(du2J) mutation results in a 2 bp deletion in the coding region and a complete loss of alpha2delta-2 protein. Here we show that du(2J)/du(2J) mice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22 degrees C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34 degrees C, du(2J)/du(2J) PCs show no spontaneous intrinsic activity. Du(2J)/du(2J) mice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du(2J)/+ mice have a marked reduction in alpha2delta-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tyrosine hydroxylase gene expression. However, du(2J)/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in alpha2delta-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of alpha2delta-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.
Donato
Roberta
R
Department of Physiology, University College London, London WC1E 6BT, United Kingdom.
Page
Karen M
KM
Koch
Dietlind
D
Nieto-Rostro
Manuela
M
Foucault
Isabelle
I
Davies
Anthony
A
Wilkinson
Tonia
T
Rees
Michele
M
Edwards
Frances A
FA
Dolphin
Annette C
AC
D000818:Animals; D019556:COS Cells; D015220:Calcium Channels / Q000235:genetics* / Q000502:physiology; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000235:genetics*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology*
C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels