Martijn Schonewille

Martijn Schonewille
Erasmus MC | Erasmus MC · Department of Neuroscience

PhD

About

76
Publications
12,957
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
3,456
Citations
Citations since 2016
32 Research Items
2140 Citations
20162017201820192020202120220100200300
20162017201820192020202120220100200300
20162017201820192020202120220100200300
20162017201820192020202120220100200300
Additional affiliations
September 2011 - February 2016
Erasmus MC
Position
  • Professor (Assistant)
September 2008 - September 2011
Erasmus MC
Position
  • PostDoc Position
February 2003 - September 2008
Erasmus MC
Position
  • PhD Student

Publications

Publications (76)
Preprint
The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior. Presynaptic cAMP–EPAC–PKCε signaling cascade induces a previo...
Article
Full-text available
Tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that promotes the inhibition of mechanistic target of rapamycin (mTOR) pathway, and mutations in TSC1 lead to a rare complex disorder of the same name. Despite phenotype heterogeneity, up to 50% of TSC patients present with autism spectrum disorder (ASD). Consequently, TSC models are often u...
Preprint
Full-text available
Tuberous sclerosis complex 1 ( TSC1 ) is a tumour suppressor gene that inhibits the mechanistic target of rapamycin (mTOR) pathway. Mutations in TSC1 lead to a rare complex disorder of the same name, in which up to 50% of patients present with autism spectrum disorder (ASD). ASD is a highly prevalent, early-onset neurodevelopmental disorder, charac...
Article
Full-text available
Purkinje cells (PCs) in the cerebellar cortex can be divided into at least two main subpopulations: one subpopulation that prominently expresses ZebrinII (Z+), and shows a relatively low simple spike firing rate, and another that hardly expresses ZebrinII (Z–) and shows higher baseline firing rates. Likewise, the complex spike responses of PCs, whi...
Article
Full-text available
Significance Learning depends on synaptic plasticity. The signaling mechanisms that control induction of plasticity determine the learning rules at the specific synapse involved. Moreover, the relationship between the activity patterns of synaptic inputs and the type, direction, and level of plasticity induced may evolve during development. Here, w...
Article
Full-text available
Significance Neuronal subtypes are differentially affected by neuropathologies. For example, Purkinje cells, the principal neurons of the cerebellum, can be divided in subpopulations based on their sensitivity to pathological insult. However, the molecular mechanisms explaining why, among seemingly identical neurons, some will degenerate while othe...
Article
Full-text available
Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy deve...
Article
Full-text available
Protein phosphatase 2B (PP2B) is critical for synaptic plasticity and learning, but the molecular mechanisms involved remain unclear. Here we identified different types of proteins that interact with PP2B, among which structural proteins of the postsynaptic densities (PSDs) of Purkinje cells (PCs) in mice of either se. Deleting PP2B reduced express...
Article
Full-text available
Distinct populations of Purkinje cells (PCs) with unique molecular and connectivity features are at the core of the modular organization of the cerebellum. Previously, we showed that firing activity of Purkinje cells differs between ZebrinII-positive (Z+) and -negative (Z−) cerebellar modules (Zhou et al., 2014; Wu et al., 2019). Here, we investiga...
Article
Full-text available
Purkinje cells are the primary processing units of the cerebellar cortex and display molecular heterogeneity that aligns with differences in physiological properties, projection patterns, and susceptibility to disease. In particular, multiple mouse models that feature Purkinje cell degeneration are characterized by incomplete and patterned Purkinje...
Preprint
Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional...
Article
Full-text available
The majority of excitatory postsynaptic currents in the brain are gated through AMPA-type glutamate receptors, the kinetics and trafficking of which can be modulated by auxiliary proteins. It remains to be elucidated whether and how auxiliary proteins can modulate synaptic function to contribute to procedural memory formation. In this study, we rep...
Article
Full-text available
Neurons store information by changing synaptic input weights. In addition, they can adjust their membrane excitability to alter spike output. Here, we demonstrate a role of such “intrinsic plasticity” in behavioral learning in a mouse model that allows us to detect specific consequences of absent excitability modulation. Mice with a Purkinje-cell–s...
Article
Full-text available
Despite the canonical homogeneous character of its organization, the cerebellum plays differential computational roles in distinct sensorimotor behaviors. Previously we showed that Purkinje cell activity differs between zebrin-negative (Z-) and zebrin-positive (Z+) modules (Zhou et al., 2014). Here, using gain-of-function and loss-of-function mouse...
Preprint
Full-text available
Despite the canonical homogenous character of its organization, the cerebellum plays differential computational roles in distinct types of sensorimotor behaviors. However, the molecular and cell physiological underpinnings are unclear. Here we determined the contribution of transient receptor potential cation channel type C3 (TRPC3) to signal proce...
Article
Full-text available
The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give t...
Article
Full-text available
In the original version of this paper, the Title should have been written with "A Consensus paper" to read "Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper".
Article
Full-text available
The basal interstitial nucleus (BIN) in the white matter of the vestibulocerebellum has been defined more than three decades ago, but has since been largely ignored. It is still unclear which neurotransmitters are being used by BIN neurons, how these neurons are connected to the rest of the brain and what their activity patterns look like. Here, we...
Preprint
Full-text available
Unstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable. We generated a novel knock-in mouse line with CAG100 expansion in Atxn2 , transmitted uns...
Article
Full-text available
In many brain regions involved in learning NMDA receptors (NMDARs) act as coincidence detectors of pre- and postsynaptic activity, mediating Hebbian plasticity. Intriguingly, the parallel fiber (PF) to Purkinje cell (PC) input in the cerebellar cortex, which is critical for procedural learning, shows virtually no postsynaptic NMDARs. Why is this? H...
Chapter
Single-unit recordings in vivo are the unitary elements in the processing of the brain and as such essential in systems physiology to understand brain functioning. In the cerebellum, a structure with high levels of intrinsic activity, studying these elements in vivo in an awake animal is imperative to obtain information regarding the processing fea...
Article
Full-text available
Anodal direct current stimulation (DCS) of the cerebellum facilitates adaptation tasks, but the mechanism underlying this effect is poorly understood. We have evaluated whether the effects of DCS effects depend on plasticity of cerebellar Purkinje cells (PCs). Here, we have successfully developed a mouse model of cerebellar DCS, allowing us to pres...
Data
Movie S2. Recording conditions during VOR decrease and increase training Combined visual and vestibular stimulation for gain‐decrease and gain‐increase training. Probe trials were executed as can be seen from Movie S1 during VOR. Note that, for the purpose of the movie, the light conditions were changed. Under experimental conditions, there were n...
Article
Full-text available
Key points Directionality, inherent to movements, has behavioural and neuronal correlates. Direction of vestibular stimulation determines motor learning efficiency. Vestibulo‐ocular reflex gain–increase correlates with Purkinje cell simple spike potentiation. The locus of neural correlates for vestibulo‐ocular reflex adaptation is paradigm specific...
Article
Full-text available
Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavio...
Article
Full-text available
Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) re...
Data
Supplementary Figures 1-7 and Supplementary Table 1
Article
Full-text available
Chloride homeostasis determines the impact of inhibitory synaptic transmission and thereby mediates the excitability of neurons. Even though cerebellar Purkinje cells (PCs) receive a pronounced inhibitory GABAergic input from stellate and basket cells, the role of chloride homeostasis in these neurons is largely unknown. Here we studied at both the...
Article
Full-text available
Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo-ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3am-/p+...
Article
Full-text available
Fragile X-associated tremor/ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of the fragile X-premutation who have an expanded CGG repeat in the 5'-UTR of the FMR1 gene. FXTAS is characterized by progressive development of intention tremor, ataxia, parkinsonism and neuropsychological problems. The disease is tho...
Article
Full-text available
The massive computational capacity of the cerebellar cortex is conveyed by Purkinje cells onto cerebellar and vestibular nuclei neurons through their GABAergic, inhibitory output. This implies that pauses in Purkinje cell simple spike activity are potentially instrumental in cerebellar information processing, but their occurrence and extent are sti...
Article
Full-text available
Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with th...
Article
Full-text available
Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred c...
Article
Full-text available
Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred c...
Article
Full-text available
Significance T-type calcium channels are present in the spines of a number of principal neurons. In absence of specific antagonists, their function has been difficult to elucidate. At the cerebellar synapse between parallel fiber (PF) and Purkinje cell (PC), postsynaptic Ca ²⁺ signaling is not the result of ionotropic glutamatergic receptor activat...
Article
Full-text available
The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests th...
Article
Full-text available
The cerebellum fine-tunes motor activity via its Purkinje cell output. Purkinje cells produce two different types of spikes, complex spikes and simple spikes, which often show reciprocal activity: a periodical increase in complex spikes is associated with a decrease in simple spikes, and vice versa. This reciprocal firing is thought to be essential...
Article
Full-text available
Cerebellar granule cells (GCs) account for more than half of all neurons in the CNS of vertebrates. Theoretical work has suggested that the abundance of GCs is advantageous for sparse coding during memory formation. Here, we minimized the output of the majority of GCs by selectively eliminating their CaV2.1 (P/Q-type) Ca(2+) channels, which mediate...
Article
Full-text available
Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted...
Article
Full-text available
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 cereb...
Article
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 imp...
Article
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disease, characterized by various neurocutaneous symptoms, cognitive impairments and problems in fine and gross motor performance. Although cognitive deficits in NF1 have been attributed to increased release of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the hipp...
Article
In recent years there has been an increased interest in the function of inhibitory interneurons. In the cerebellum this interest has been paired with successes in obtaining recordings from these neurons in vivo and genetic manipulations to probe their function during behavioral tasks such as motor learning. This review focuses on a synthesis of rec...
Article
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 activitie...
Data
Reduced internuclear commissure in Robo3-deficient mice. (A–F) Coronal section of P0 brains immunostained with Hb9 following DiI tracing of the VI–III internuclear connection. In controls (A and B), the internuclear commissure is strongly labeled (arrow), and DiI-labeled cells are observed at the level of the abducens nucleus (VI). (C and D) In Kro...
Data
Normal cerebellar cortex and pontine nuclei in Ptf1a::cre;Robo3lox/lox mice (A–D) Sagittal sections of the cerebellar cortex of P32 control (A and C) and Ptf1a::cre;Robo3lox/lox mice (B and D) labeled with antibodies against parvalbumin (Parv) and calbindin (CaBP) and counterstained with Hoechst. Purkinje cells coexpress the two proteins, whereas m...
Data
Expression pattern of midline-derived axon guidance factors. Coronal sections at the level of rhombomere 5 of E11 embryos hybridized with riboprobes for Netrin1 (A and C), Shh (C and D), Slit1 (E and F), Slit2 (G and H), and Slit3 (I and J). The expression pattern is similar in controls and Krox20::cre;Robo3lox/lox embryos. Controls are either Robo...
Data
ABR thresholds and binaural difference in control and Krox20::cre;Robo3lox/lox mice. (A) The detection thresholds of ABR did not significantly differ in Krox20::cre;Robo3lox/lox versus control mice and remained in the normal range from 5–40 kHz. (B) The binaural-difference wave complex resulting from the fact that the late ABR waves in response to...
Data
Normal spinal cord commissures in Ptf1a::cre;Robo3lox/lox embryos. (A–H) are coronal sections of the spinal cord of E13 embryos immunolabeled with neurofilament and Robo3 (A, B, E, and F) or TAG-1 and Robo3 (C, D, G, and H). Commissures are not reduced and still express Robo3 in Ptf1a::cre;Robo3lox/lox mice. Scale bars represent 200 µm. (2.74 MB TI...
Data
Supplemental Methods. Eye movement and ABR recordings. (0.02 MB DOC)
Data
Ataxic gait of Ptf1a::cre;Robo3lox/lox mice. Two P15 littermates: the Ptf1a::cre;Robo3lox/+ mouse walks normally, whereas the Ptf1a::cre;Robo3lox/lox mouse has an ataxic gait. (1.36 MB MOV)