Neurons are generally considered to communicate information by increasing or decreasing their firing rate. However, in principle, they could in addition convey messages by using specific spatiotemporal patterns of spiking activities and silent intervals. Here, we review expanding lines of evidence that such spatiotemporal coding occurs in the cerebellum, and that the olivocerebellar system is optimally designed to generate and employ precise patterns of complex spikes and simple spikes during the acquisition and consolidation of motor skills. These spatiotemporal patterns may complement rate coding, thus enabling precise control of motor and cognitive processing at a high spatiotemporal resolution by fine-tuning sensorimotor integration and coordination.

Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.

SummaryThree decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval.

Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRdelta2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19-31], was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex.