Impaired Motor Learning in the Vestibulo-Ocular Reflex in Mice with Multiple Climbing Fiber Input to Cerebellar Purkinje Cells

Abstract

A unique feature of the cerebellar architecture is that Purkinje cells in the cerebellar cortex each receive input from a single climbing fiber. In mice deficient in the ␥ isoform of protein kinase C (PKC␥ Ϫ/Ϫ mice), this normal architecture is disrupted so that individual Purkinje cells receive input from multiple climbing fibers. These mice have no other known abnormalities in the cerebellar circuit. Here, we show that PKC␥ Ϫ/Ϫ mice are profoundly impaired in vestibulo-ocular reflex (VOR) motor learning. The PKC␥ Ϫ/Ϫ mice exhibited no adaptive increases or decreases in VOR gain at training frequencies of 2 or 0.5 Hz. This impairment was present across a broad range of peak retinal slip speeds during training. We compare the results for VOR motor learning with previous studies of the performance of PKC␥ Ϫ/Ϫ mice on other cerebellum-dependent learning tasks. Together, the results suggest that single climbing fiber innervation of Purkinje cells is critical for some, but not all, forms of cerebellum-dependent learning, and this may depend on the region of the cerebellum involved, the organization of the relevant neural circuits downstream of the cerebellar cortex, as well as the timing requirements of the learning task.

Magnetic eye tracking in mice

“…Likewise, the eye movements elicited by combined vestibular and visual inputs were unaltered by magnet implantation ( Figure 6—figure supplement 1 ). The gain and phase of the VOR measured with magnetic eye tracking ( Figure 6 , dashed, blue lines ) were in the range reported previously in mice by our laboratory ( Kimpo and Raymond, 2007 ) and other laboratories ( Iwashita et al, 2001 ; van Alphen et al, 2001 ), as were the gain and phase of the visually driven eye movements elicited by an optokinetic stimulus at a range of frequencies ( Figure 6—figure supplement 2 ; Iwashita et al, 2001 ; Kimpo and Raymond, 2007 ; Tabata et al, 2010 ; van Alphen et al, 2001 , 2009 , 2010 ). Thus, magnet implantation had no detectable effect on oculomotor behavior.…”

Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism

“…Together, these observations suggest a significant, but not complete overlap in molecular mechanisms involved in LTD at PF and CF synapses in the young adult / adult brain and in developmental synapse elimination. In this context, it is interesting to note that cerebellum-dependent motor learning cannot only be impaired when LTD is absent, but also as a result of incomplete CF elimination 66 . Here, we performed patch-clamp recordings from P10-12 and P63-70 Purkinje cells to specifically examine alterations in developmental synaptic pruning.…”

Serotonergic control of Purkinje cell maturation and climbing fibre elimination by 5‐HT3 receptors in the juvenile mouse cerebellum

“…It is known that persistent polyinnervation of Purkinje cells by climbing fibres leads to problems in motor learning in (young) adult mice (i.e. Kimpo & Raymond, 2007). Other mouse models with delayed but not completely impaired climbing fibre elimination, such as the αCaMKII knockout mouse line, do show motor learning deficits in adult mice (Hansel et al 2006).…”