The du 2 J mouse model of ataxia and absence epilepsy has deficient cannabinoid CB 1 receptor - mediated signalling

• Cerebellar ataxias are progressive debilitating diseases with no known treatment and are associated with defective motor function and, in particular, abnormalities to Purkinje cells. • Mutant mice with deficits in Ca 2+ channel auxiliary α2δ-2 subunits are used as models of cerebellar ataxia. • Our data in the du 2J mouse model shows an association between the ataxic phenotype exhibited by homozygous du 2J /du 2J mice and increased irregularity of Purkinje cell firing. • We show that both heterozygous +/du 2J and homozygous du 2J /du 2J mice completely lack the strong presynaptic modulation of neuronal firing by cannabinoid CB 1 receptors which is exhibited by litter-matched control mice. • These results show that the du 2J ataxia model is associated with deficits in CB 1 receptor signalling in the cerebellar cortex, putatively linked with compromised Ca 2+ channel activity due to reduced α2δ-2 subunit expression. Knowledge of such deficits may help design therapeutic agents to combat ataxias. 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 Ca 2+ channel function. The 'ducky' du 2J mouse model of ataxia and absence epilepsy represents a clean knockout of the auxiliary Ca 2+ channel subunit, α2δ-2, and has been associated with deficient Ca 2+ channel function in the cerebellar cortex. Here, we investigate effects of du 2J mutation on PC layer (PCL) and granule cell (GC) 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. 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 CB 1 receptor (CB 1 R)-mediated modulation of spontaneous neuronal spike firing and CB 1 R-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 CB 1 R expression. …