RIM4 deficiency leads to disturbed dendritic arborization and altered somato-dendritic excitability of cerebellar Purkinje cells
1 Department of Neurosurgery, Bonn University Medical School, 53105 Bonn, Germany; Institute of Neuropathology, Bonn University Medical School, 53105 Bonn, Germany
2 Institute of Neuropathology, Bonn University Medical School, 53105 Bonn, Germany
3 Department of Neurosurgery, Bonn University Medical School, 53105 Bonn, Germany
At the synaptic active zone, Rab3-interacting molecules 1 and 2 (RIM/2s) are one of the central scaffold proteins interacting with synaptic vesicles, Ca2+ channels and also with other synaptic proteins. On the other hand, the functional role of the short RIM isoforms, RIM3 and RIM4, is not understood yet. RIM4 deficient mice develop an episodic motor phenotype characterized by impaired motor coordination. We found that, compared to wild-type mice, RIM4 KO mice showed a reduced cerebellar area and a decreased dendritic arborization of Purkinje cells (PCs). Next, we investigated if ablation of RIM4 solely in PCs would resemble the phenotype found in the constitutive KO by crossing newly generated conditional RIM4 KO to a PC-specific Cre-driver line (PCP2-Cre). PCP2-RIM4 KO mice exhibited episodic motor impairments, a cerebellar area loss, reduced dendritic arborization, and disturbed rhythmic spontaneous activity of PCs similar to the constitutive KO mice. Since it was reported before that caffeine injections induce motor episodes in ataxia mouse models, we applied this in our mouse models and demonstrated a reduction in pace-making activity of PCs upon an in vitro caffeine application. Re-expression of RIM4 via injections of rAAV viral particles into the cerebellar vermis in RIM4 deficient mice rescued the knock-out phenotype at the cellular level in both newborn and adult animals. Taken together, our results show that RIM4 is required for normal dendritic arborization and intrinsic electrical properties of PCs, and that the alterations induced in PCs by the absence of RIM4 cause the episodic motor phenotype.