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 (GC) layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneuron-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 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.

PMID:

 

23732642

 

[PubMed – as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/23732642