http://repub.eur.nl/res/aut/7659/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/34334/ 2011-12-01T00:00:00Z http://repub.eur.nl/res/pub/34335/ 2011-12-01T00:00:00Z Neurons in the cerebellar nuclei (CN) receive inhibitory inputs from Purkinje cells in the cerebellar cortex and provide the major output from the cerebellum, but their computational function is not well understood. It has recently been shown that the spike activity of Purkinje cells is more regular than previously assumed and that this regularity can affect motor behaviour. We use a conductance-based model of a CN neuron to study the effect of the regularity of Purkinje cell spiking on CN neuron activity. We find that increasing the irregularity of Purkinje cell activity accelerates the CN neuron spike rate and that the mechanism of this recoding of input irregularity as output spike rate depends on the number of Purkinje cells converging onto a CN neuron. For high convergence ratios, the irregularity induced spike rate acceleration depends on short-term depression (STD) at the Purkinje cell synapses. At low convergence ratios, or for synchronised Purkinje cell input, the firing rate increase is independent of STD. The transformation of input irregularity into output spike rate occurs in response to artificial input spike trains as well as to spike trains recorded from Purkinje cells in tottering mice, which show highly irregular spiking patterns. Our results suggest that STD may contribute to the accelerated CN spike rate in tottering mice and they raise the possibility that the deficits in motor control in these mutants partly result as a pathological consequence of this natural form of plasticity. http://repub.eur.nl/res/pub/34381/ 2011-06-01T00:00:00Z 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. http://repub.eur.nl/res/pub/33968/ 2011-04-14T00:00:00Z Long-term depression at parallel fiber-Purkinje cell synapses (PF-PC LTD) has been proposed to be required for cerebellar motor learning. To date, tests of this hypothesis have sought to interfere with receptors (mGluR1) and enzymes (PKC, PKG, or αCamKII) necessary for induction of PF-PC LTD and thereby determine if cerebellar motor learning is impaired. Here, we tested three mutant mice that target the expression of PF-PC LTD by blocking internalization of AMPA receptors. Using three different cerebellar coordination tasks (adaptation of the vestibulo-ocular reflex, eyeblink conditioning, and locomotion learning on the Erasmus Ladder), we show that there is no motor learning impairment in these mutant mice that lack PF-PC LTD. These findings demonstrate that PF-PC LTD is not essential for cerebellar motor learning. http://repub.eur.nl/res/pub/21069/ 2010-08-01T00:00:00Z Cerebellar motor learning is required to obtain procedural skills. Studies have provided supportive evidence for a potential role of kinase-mediated long-term depression (LTD) at the parallel fiber to Purkinje cell synapse in cerebellar learning. Recently, phosphatases have been implicated in the induction of potentiation of Purkinje cell activities in vitro, but it remains to be shown whether and how phosphatase-mediated potentiation contributes to motor learning. Here, we investigated its possible role by creating and testing a Purkinje cell-specific knockout of calcium/calmodulin-activated protein-phosphatase-2B (L7-PP2B). The selective deletion of PP2B indeed abolished postsynaptic long-term potentiation in Purkinje cells and their ability to increase their excitability, whereas LTD was unaffected. The mutants showed impaired "gain-decrease" and "gain-increase" adaptation of their vestibulo-ocular reflex (VOR) as well as impaired acquisition of classical delay conditioning of their eyeblink response. Thus, our data indicate that PP2B may indeed mediate potentiation in Purkinje cells and contribute prominently to cerebellar motor learning. http://repub.eur.nl/res/pub/27279/ 2010-05-04T00:00:00Z The output of the cerebellar cortex is controlled by two main inputs, (i.e., the climbing fiber and mossy fiber-parallel fiber pathway) and activations of these inputs elicit characteristic effects in its Purkinje cells: that is, the so-called complex spikes and simple spikes. Target neurons of the Purkinje cells in the cerebellar nuclei show rebound firing, which has been implicated in the processing and storage of motor coordination signals. Yet, it is not known to what extent these rebound phenomena depend on different modes of Purkinje cell activation. Using extracellular as well as patch-clamp recordings, we show here in both anesthetized and awake rodents that simple and complex spike-like train stimuli to the cerebellar cortex, as well as direct activation of the inferior olive, all result in rebound increases of the firing frequencies of cerebellar nuclei neurons for up to 250 ms, whereas single-pulse stimuli to the cerebellar cortex predominantly elicit well-timed spiking activity without changing the firing frequency of cerebellar nuclei neurons. We conclude that the rebound phenomenon offers a rich and powerful mechanism for cerebellar nuclei neurons, which should allow them to differentially process the climbingfiber andmossyfiber inputs in a physiologically operating cerebellum. http://repub.eur.nl/res/pub/27904/ 2010-03-11T00:00:00Z Objective: The CACNA1A gene encodes the pore-forming subunit of neuronal Cav2.1 Ca2+channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma. Methods: We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences. Results: Cacna1aS218Lmice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage-dependent negative shift in voltage dependence of Cav2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1aS218Lmice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus. Interpretation: The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema. http://repub.eur.nl/res/pub/24587/ 2009-08-01T00:00:00Z Although feedforward inhibition onto Purkinje cells was first documented 40 years ago, we understand little of how inhibitory interneurons contribute to cerebellar function in behaving animals. Using a mouse line (PC-Δγ2) in which GABA A receptor-mediated synaptic inhibition is selectively removed from Purkinje cells, we examined how feedforward inhibition from molecular layer interneurons regulates adaptation of the vestibulo-ocular reflex. Although impairment of baseline motor performance was relatively mild, the ability to adapt the phase of the vestibulo-ocular reflex and to consolidate gain adaptations was strongly compromised. Purkinje cells showed abnormal patterns of simple spikes, both during and in the absence of evoked compensatory eye movements. On the basis of modeling our experimental data, we propose that feedforward inhibition, by controlling the fine-scale patterns of Purkinje cell activity, enables the induction of plasticity in neurons of the cerebellar and vestibular nuclei. http://repub.eur.nl/res/pub/22574/ 2009-07-01T00:00:00Z Abstract We found that betaCaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the parallel fiber-Purkinje cell synapse; a protocol that induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation. http://repub.eur.nl/res/pub/22573/ 2009-06-07T00:00:00Z We found that betaCaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the parallel fiber-Purkinje cell synapse; a protocol that induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation. http://repub.eur.nl/res/pub/30321/ 2008-12-01T00:00:00Z Homozygous tottering mice are spontaneous ataxic mutants, which carry a mutation in the gene encoding the ion pore of the P/Q-type voltage-gated calcium channels. P/Q-type calcium channels are prominently expressed in Purkinje cell terminals, but it is unknown to what extent these inhibitory terminals in tottering mice are affected at the morphological and electrophysiological level. Here, we investigated the distribution and ultrastructure of their Purkinje cell terminals in the cerebellar nuclei as well as the activities of their target neurons. The densities of Purkinje cell terminals and their synapses were not significantly affected in the mutants. However, the Purkinje cell terminals were enlarged and had an increased number of vacuoles, whorled bodies, and mitochondria. These differences started to occur between 3 and 5 weeks of age and persisted throughout adulthood. Stimulation of Purkinje cells in adult tottering mice resulted in inhibition at normal latencies, but the activities of their postsynaptic neurons in the cerebellar nuclei were abnormal in that the frequency and irregularity of their spiking patterns were enhanced. Thus, although the number of their terminals and their synaptic contacts appear quantitatively intact, Purkinje cells in tottering mice show several signs of axonal damage that may contribute to altered postsynaptic activities in the cerebellar nuclei. http://repub.eur.nl/res/pub/29835/ 2008-06-12T00:00:00Z Cerebellar high-frequency oscillations have been observed for many decades, but their underlying mechanisms have remained enigmatic. In this issue of Neuron, two papers indicate that specific intrinsic mechanisms in the cerebellar cortex contribute to the generation of these oscillations. Middleton et al. show that GABAAreceptor activation and nonchemical transmission are required for nicotine-dependent oscillations at 30-80 Hz and 80-160 Hz, respectively, while de Solages et al. provide evidence that recurrent inhibition by Purkinje cells is essential for oscillations around 200 Hz. http://repub.eur.nl/res/pub/37144/ 2007-05-30T00:00:00Z Background. Cerebellar Purkinje cells (PC) in vivo are commonly reported to generate irregular spike trains, documented by high coefficients of variation of interspike-intervals (ISI). In strong contrast, they fire very regularly in the in vitro slice preparation. We studied the nature of this difference in firing properties by focusing on short-term variability and its dependence on behavioral state. Methodology/Principal Findings. Using an analysis based on CV2values, we could isolate precise regular spiking patterns, lasting up to hundreds of milliseconds, in PC simple spike trains recorded in both anesthetized and awake rodents. Regular spike patterns, defined by low variability of successive ISIs, comprised over half of the spikes, showed a wide range of mean ISIs, and were affected by behavioral state and tactile stimulation. Interestingly, regular patterns often coincided in nearby Purkinje cells without precise synchronization of individual spikes. Regular patterns exclusively appeared during the up state of the PC membrane potential, while single ISIs occurred both during up and down states. Possible functional consequences of regular spike patterns were investigated by modeling the synaptic conductance in neurons of the deep cerebellar nuclei (DCN). Simulations showed that these regular patterns caused epochs of relatively constant synaptic conductance in DCN neurons. Conclusions/Significance. Our findings indicate that the apparent irregularity in cerebellar PC simple spike trains in vivo is most likely caused by mixing of different regular spike patterns, separated by single long intervals, over time. We propose that PCs may signal information, at least in part, in regular spike patterns to downstream DCN neurons. http://repub.eur.nl/res/pub/36289/ 2007-04-05T00:00:00Z Many theories of cerebellar function assume that long-term depression (LTD) of parallel fiber (PF) synapses enables Purkinje cells to learn to recognize PF activity patterns. We have studied the LTD-based recognition of PF patterns in a biophysically realistic Purkinje-cell model. With simple-spike firing as observed in vivo, the presentation of a pattern resulted in a burst of spikes followed by a pause. Surprisingly, the best criterion to distinguish learned patterns was the duration of this pause. Moreover, our simulations predicted that learned patterns elicited shorter pauses, thus increasing Purkinje-cell output. We tested this prediction in Purkinje-cell recordings both in vitro and in vivo. In vitro, we found a shortening of pauses when decreasing the number of active PFs or after inducing LTD. In vivo, we observed longer pauses in LTD-deficient mice. Our results suggest a novel form of neural coding in the cerebellar cortex. http://repub.eur.nl/res/pub/22474/ 2006-01-01T00:00:00Z CONTEXT: The recent focus on the development of preventive interventions for Alzheimer disease has fueled the search for biomarkers of presymptomatic disease. Patients with Alzheimer disease and mild cognitive impairment have marked atrophy of the hippocampus and amygdala compared with healthy elderly people. Whether atrophy of these structures is also present in persons without cognitive impairment who later develop dementia is unknown. OBJECTIVE: To assess whether volumetric assessment of the hippocampus and amygdala using magnetic resonance imaging (MRI) predicts dementia in elderly people without cognitive impairment. DESIGN: Longitudinal cohort study. SETTING: A general community in the Netherlands. PARTICIPANTS: Five hundred eleven persons, aged 60 to 90 years, free of dementia at baseline were followed up during 3043 person-years (mean per person, 6.0 years). We performed volumetric assessment of the hippocampus and amygdala, obtained information about daily memory problems, and performed extensive neuropsychological testing in all study participants. MAIN OUTCOME MEASURE: Dementia, as assessed by repeated neuropsychological screening and monitoring of medical records. RESULTS: Thirty-five persons developed dementia (26 with Alzheimer disease). Hippocampal and amygdalar volumes were strongly associated with the risk of dementia; the age-, sex-, and education-adjusted hazard ratio per 1-SD decrease in volume was 3.0 (95% confidence interval, 2.0-4.6) for the hippocampus and 2.1 (95% confidence interval, 1.5-2.9) for the amygdala. The hazard ratios associated with atrophy were similar in persons without memory complaints or low cognitive function at baseline. Compared with those remaining free of dementia, baseline brain volumes were 17% smaller in persons who received a clinical diagnosis of dementia within 2 to 3 years after MRI and still 5% smaller in those whose conditions were diagnosed 6 years after MRI. CONCLUSION: Atrophy of the hippocampus and amygdala on MRI in cognitively intact elderly people predicts dementia during a 6-year follow-up. http://repub.eur.nl/res/pub/6741/ 2005-03-23T00:00:00Z