title: The du(2J) mouse model of ataxia and absence epilepsy has deficient cannabinoid CB₁ receptor-mediated signalling.
abstract: Cerebellar ataxias are a group of progressive, debilitating diseases often associated with abnormal Purkinje cell (PC) firing and/or degeneration. Many animal models of cerebellar ataxia display abnormalities in Ca²⁺ channel function. The 'ducky' du(2J) mouse model of ataxia and absence epilepsy represents a clean knock-out of the auxiliary Ca²⁺ channel subunit α2δ-2, and has been associated with deficient Ca²⁺ channel function in the cerebellar cortex. Here, we investigate effects of du(2J) mutation on PC layer (PCL) and granule cell layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneurone-Purkinje cell (IN-PC) synapses. Increased neuronal firing irregularity was seen in the PCL and, to a less marked extent, in the GCL in du(2J)/du(2J), but not +/du(2J), mice; these data suggest that the ataxic phenotype is associated with lack of precision of PC firing, that may also impinge on GC activity and requires expression of two du(2J) alleles to manifest fully. The du(2J) mutation had no clear effect on spontaneous inhibitory postsynaptic current (sIPSC) frequency at IN-PC synapses, but was associated with increased sIPSC amplitudes. du(2J) mutation ablated cannabinoid CB1 receptor (CB1R)-mediated modulation of spontaneous neuronal spike firing and CB1R-mediated presynaptic inhibition of synaptic transmission at IN-PC synapses in both +/du(2J) and du(2J)/du(2J) mutants, effects that occurred in the absence of changes in CB1R expression. These results demonstrate that the du(2J) ataxia model is associated with deficient CB1R signalling in the cerebellar cortex, putatively linked with compromised Ca²⁺ channel activity and the ataxic phenotype.
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, PO Box 228, Reading RG6 6AJ, UK.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Whalley
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stephens
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics; D002524:Cerebellar Ataxia / Q000503:physiopathology*; D002525:Cerebellar Cortex / Q000502:physiology*; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D015398:Signal Transduction; D009435:Synaptic Transmission
chemical_list: C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D043884:Receptor, Cannabinoid, CB1