Cerebellar ataxias comprise a group of progressive neurological diseases associated with deficits in motor coordination and are typically associated with dysfunction and/or degeneration of Purkinje cells (PCs), the sole efferent output of the cerebellar cortex. Cannabinoid CB1 receptors (CB1Rs) represent the most widespread G-protein-coupled receptor population in the mammalian cerebellum. CB1Rs are present on inhibitory, predominantly basket cell and stellate cell, interneurons (INs) and excitatory, predominantly parallel fibre and climbing fibre, presynaptic terminals supplying PCs. Activation of CB1Rs by endogenous cannabinoids (endocannabinoids) suppress neurotransmitter release and have been widely associated with a number of different forms of short- and long-term synaptic plasticities. Importantly, activation of presynaptic CB1Rs has been shown to promote cerebellar dysfunction, causing severe motor incoordination (Patel & Hillard, 2001), which models the ataxic condition. Of related interest is that whilst CB1R knock-out animals do not exhibit gross defects in motor co-ordination, deficits in eyeblink conditioning, a discrete cerebellar-dependent, motor learning process, have been reported (Kishimoto & Kano, 2006). Together, these data suggest that CB1Rs may modulate cerebellar circuitry in ataxic disease. We (and others) have shown that activation of CB1Rs at IN-PC synapses causes a reduction in the frequency of spontaneous and miniature inhibitory postsynaptic currents, and that CB1R antagonist action is consistent with the presence of a significant endocannabinergic tone in the cerebellar cortex (Ma et al., 2008). We have also used multi-electrode array recording to demonstrate that CB1R ligand-induced changes to cerebellar cortex network activity are mediated via effects on inhibitory synaptic transmission (Ma et al., 2008). It is likely that CB1Rs couple to presynaptic CaV2.1 (P/Q-type) voltage-dependent calcium channels at IN-PC synapses and also have direct effects on the synaptic vesicle machinery to mediate reductions in quantal GABA release (as discussed in Wang et al., 2013). We have also shown that the allosteric CB1R antagonist PSNCBAM-1 has differential, CB1R agonist-dependent actions at IN-PC synapses (Wang et al., 2011). These data point to functional selectivity of allosteric antagonists in the cerebellum and suggest that CB1Rs contain both orthosteric and allosteric sites that may be targeted in disease.A number of mouse mutant models with specific ion channel subunit deficits exhibit different forms of ataxia. A well-described mouse mutant is the ‘ducky2J’ (du2J) model, which has a 2 base pair deletion in exon 9 of the Cacna2d2 gene, which results in the complete ablation of α2δ2 accessory voltage-dependent calcium channel subunits in the cerebellar cortex (Brodbeck et al., 2002). du2J mice typically exhibit smaller than normal size, an ataxia phenotype, absence seizures and paroxysmal dyskinesia and are associated with reduced Cav2.1 current and, in common, with other ataxic mutants, an increased irregularity of PC firing (Brodbeck et al., 2002; Donato et al. 2006). We have shown that du2J mice exhibit increased irregularity of PC and, to a lesser extent, granule cell, firing in multi-electrode array recordings from cerebellar brain slices (Wang et al., 2013). Of note was that clear effects on PC firing regularity in du2J/du2J mice were not seen in heterozygous +/du2J mice, the latter also lack a clear behavioural ataxic phenotype. Importantly, the CB1R-mediated presynaptic inhibition at IN-PC synapses seen in litter-matched controls was completely absent in both +/du2J and du2J/du2J mice. These data demonstrate that ataxic α2δ2-deficient mice have aberrant CB1R-mediated signalling that could contribute to disease and that progressive deficits may underlie the ataxic phenotype (Wang et al. 2013). Deficient CB1R-mediated signalling occurred in the absence of gross changes to CB1R expression in the cerebellar cortex and is suggested to occur due to compromised calcium channel activity consequential to reduced α2δ2 expression in du2J mice. In the future, it will be of interest to determine if deficits in CB1R-mediated signalling are hallmark characteristics of different forms of ataxia and if aberrant cannabinergic signalling represents a useful biomarker for early or asymptomatic cerebellar dysfunction.