Cerebellar Plasticity in Health and Disease

The cerebellum helps fine-tuning movements by evaluating disparities between intention and action, in order to adjust the execution of movements ‘online’, and to keep movements calibrated in the long term. The cerebellar capacity to store information, which provides the ‘memory’ needed for the recalibration of movements, the learning of new motor skills, and associative learning, is provided by modifications in the strength of synaptic couplings between neurons in the cerebellar circuitry (‘synaptic plasticity’). Cerebellar coordination and motor learning can be affected by degenerative processes, such as paraneoplastic cerebellar ataxia (PCA). This is a severe side effect of certain forms of cancer, usually characterized by the degeneration of Purkinje cells, which provide the sole output of the cerebellar cortex. PCA is associated with the expression of antineuronal autoantibodies. In chapters 2 and 3 we describe two patients with Hodgkin’s disease and PCA associated with a previously undescribed autoantibody against the metabotropic glutamate receptor type 1 (mGluR1). This autoantibody directly interferes with receptor function in vitro, affecting synaptic transmission and spontaneous Purkinje neuronal firing behavior, as well as inhibiting the induction of long-term depression of the parallel fiber to Purkinje cell synapse (PF-LTD), a form of synaptic plasticity widely associated with motor learning. Infusion of these anti-mGluR1 autoantibodies into the cerebellum of mice causes severe, reversible ataxia, indicating that PCA autoantibodies can directly affect Purkinje neuronal function by blocking receptors. Post-mortem analysis of one mGluR1-PCA patient’s cerebellum reveals a reduction in the number of Purkinje cells after chronic exposition to anti-mGluR1 autoantibodies. Together these results indicate that the anti-mGluR1 autoantibodies can cause ataxia by acutely interfering with neuronal function and synaptic plasticity, as well as through a chronic degenerative effect on cerebellar Purkinje cells. The block of PF-LTD by the anti-mGluR1 autoantibodies was also shown to affect the patients’ ability to recalibrate motor output. Cerebellar motor learning in the patients was assessed using a saccade adaptation paradigm, in which the amplitude of voluntary fast eye movements (‘saccades’) is gradually changed by systematically displacing a target during a series of consecutive saccades. Although their saccade performance was within the normal range, the capability to gradually adapt saccade amplitude was impaired in the patients with anti-mGluR1 autoantibodies, adding to the body of evidence that PF-LTD underlies forms of motor learning. In chapter 4, further analysis of saccade adaptation characteristics in humans indicates that this form of motor learning conforms to learning rules similar to those of cerebellar synaptic plasticity processes. The time course of induction and the error-based character of saccade adaptation are in line with the properties of cerebellar synaptic plasticity forms, such as PF-LTD. In chapters 5 and 6, the cellular mechanisms putatively underlying cerebellar motor learning were further explored by studying synaptic plasticity in vitro. PF-LTD can be induced by coactivation of parallel fiber (PF) and climbing fiber (CF) input at low frequencies, and is expressed as a reduction in AMPA glutamate receptors on the postsynaptic membrane. This selectively decreases the effect of glutamate released by the PFs that were concurrently active with the CF. In order to prevent synapse saturation and to allow reversal of motor learning, this reduction of PF-Purkinje cell synaptic strength must be counterbalanced by a form of potentiation that is also expressed postsynaptically. This modification, called long-term potentiation of the PF – Purkinje cell synapse (PF-LTP), can be induced by tetanizing only the PF at low frequencies. CF¬evoked calcium transients into the Purkinje cell are shown to be the polarity switch factor making the difference between PF-LTD and PF-LTP induction. Long-term depression of synaptic strength can also be induced at the CF – Purkinje cell synapse (CF-LTD), by high-frequent CF activity. CF-LTD reduces the amplitude of the CF¬evoked calcium transient, which is shown to inhibit the induction of PF-LTD. The concept arises that the cerebellar circuitry uses multiple interacting mechanisms to calibrate its output

A Balanced Translocation Disrupting BCL2L10 and PNLDC1 Segregates With Affective Psychosis

Affective psychoses are a group of severe psychiatric disorders, including schizoaffective disorder and bipolar I disorder, together affecting ∼1% of the population. Despite their high heritability, the molecular genetics and neurobiology of affective psychosis remain largely elusive. Here, we describe the identification of a structural genetic variant segregating with affective psychosis in a family with multiple members suffering from bipolar I disorder or schizoaffective disorder, bipolar type. A balanced translocation involving chromosomes 6 and 15 was detected by karyotyping and fluorescence in‐situ hybridization (FISH). Using whole‐genome sequencing, we rapidly delineated the translocation breakpoints as corresponding intragenic events disrupting BCL2L10 and PNLDC1. These data warrant further consideration for BCL2L10 and PNLDC1 as novel candidates for affective psychosis. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc

Music to prevent deliriUm during neuroSurgerY (MUSYC) Clinical trial:A study protocol for a randomised controlled trial

INTRODUCTION: Delirium is a neurocognitive disorder characterised by an acute and temporary decline of mental status affecting attention, awareness, cognition, language and visuospatial ability. The underlying pathophysiology is driven by neuroinflammation and cellular oxidative stress. Delirium is a serious complication following neurosurgical procedures with a reported incidence varying between 4% and 44% and has been associated with increased length of hospital stay, increased amount of reoperations, increased costs and mortality. Perioperative music has been reported to reduce preoperative anxiety, postoperative pain and opioid usage, and attenuates stress response caused by surgery. We hypothesize that this beneficial effect of music on a combination of delirium eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. METHODS: This protocol concerns a single-centred prospective randomised controlled trial with 6 months follow-up. All adult patients undergoing a craniotomy at the Erasmus Medical Center in Rotterdam are eligible. The music group will receive recorded music through an overear headphone before, during and after surgery until postoperative day 3. Patients can choose from music playlists, offered based on music importance questionnaires administered at baseline. The control group will receive standard of clinical care Delirium is assessed by the Delirium Observation Scale and confirmed by a delirium-expert psychiatrist according to the DSM-5 criteria. Risk factors correlated with the onset of delirium, such as cognitive function at baseline, preoperative anxiety, perioperative medication use, depth of anaesthesia and postoperative pain, and delirium-related health outcomes such as length of stay, daily function, quality of life (ie, EQ-5D, EORTC questionnaires), costs and cost-effectiveness are collected. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Center Rotterdam, The Netherlands, approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBERS: NL8503 and NCT04649450

Effects of the DICE Method to Improve Timely Recognition and Treatment of Neuropsychiatric Symptoms in Early Alzheimer's Disease at the Memory Clinic:The BEAT-IT Study

BACKGROUND: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD) and are associated with negative outcomes. However, NPS are currently underrecognized at the memory clinic and non-pharmacological interventions are scarcely implemented.OBJECTIVE: To evaluate the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) method™ to improve the care for NPS in AD at the memory clinic.METHODS: We enrolled sixty community-dwelling people with mild cognitive impairment or AD dementia and NPS across six Dutch memory clinics with their caregivers. The first wave underwent care as usual (n = 36) and the second wave underwent the DICE method (n = 24). Outcomes were quality of life (QoL), caregiver burden, NPS severity, NPS-related distress, competence managing NPS, and psychotropic drug use. Reliable change index was calculated to identify responders to the intervention. A cost-effectiveness analysis was performed and semi-structured interviews with a subsample of the intervention group (n = 12).RESULTS: The DICE method did not improve any outcomes over time compared to care as usual. Half of the participants of the intervention group (52%) were identified as responders and showed more NPS and NPS-related distress at baseline compared to non-responders. Interviews revealed substantial heterogeneity among participants regarding NPS-related distress, caregiver burden, and availability of social support. The intervention did not lead to significant gains in quality-adjusted life years and well-being years nor clear savings in health care and societal costs.CONCLUSION: The DICE method showed no benefits at group-level, but individuals with high levels of NPS and NPS-related distress may benefit from this intervention.</p

Growing up with Fragile X Syndrome: Concerns and Care Needs of Young Adult Patients and Their Parents

Little is known about care needs of young adults with Fragile X Syndrome (FXS). Patient-driven information is needed to improve understanding and support of young adults with FXS. A qualitative study was performed in 5 young adult patients (aged 18–30), and 33 parents of young adults. Concerns and care needs were categorized using the International Classifcation of Functioning, Disability, and Health. Results indicated concerns on 14 domains for males, and 13 domains for females, including physical, psychological and socio-economical issues. In both groups parents reported high stress levels and a lack of knowledge of FXS in adult care providers. This study revealed concerns on various domains, requiring gender-specifc, multidisciplinary trans

Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP

The architecture of parallel fiber axons contacting cerebellar Purkinje neurons retains spatial information over long distances. Parallel fiber synapses can trigger local dendritic calcium spikes, but whether and how this calcium signal leads to plastic changes that decode the parallel fiber input organization is unknown. By combining voltage and calcium imaging, we show that calcium signals, elicited by parallel fiber stimulation and mediated by voltage-gated calcium channels, increase non-linearly during high-frequency bursts of electrically constant calcium spikes, because they locally and transiently saturate the endogenous buffer. We demonstrate that these non-linear calcium signals, independently of NMDA or metabotropic glutamate receptor activation, can induce parallel fiber long-term potentiation. Two-photon imaging in coronal slices revealed that calcium signals inducing long-term potentiation can be observed by stimulating either the parallel fiber or the ascending fiber pathway. We propose that local dendritic calcium spikes, evoked by synaptic potentials, provide a unique mechanism to spatially decode parallel fiber signals into cerebellar circuitry changes

Control of Cerebellar Long-Term Potentiation by P-Rex-Family Guanine-Nucleotide Exchange Factors and Phosphoinositide 3-Kinase

Long-term potentiation (LTP) at the parallel fibre-Purkinje cell synapse in the cerebellum is a recently described and poorly characterized form of synaptic plasticity. The induction mechanism for LTP at this synapse is considered reciprocal to "classical" LTP at hippocampal CA1 pyramidal neurons: kinases promote increased trafficking of AMPA receptors into the postsynaptic density in the hippocampus, whereas phosphatases decrease internalization of AMPA receptors in the cerebellum. In the hippocampus, LTP occurs in overlapping phases, with the transition from early to late phases requiring the consolidation of initial induction processes by structural re-arrangements at the synapse. Many signalling pathways have been implicated in this process, including PI3 kinases and Rho GTPases.We hypothesized that analogous phases are present in cerebellar LTP, and took as the starting point for investigation our recent discovery that P-Rex--a Rac guanine nucleotide exchange factor which is activated by PtdIns(3,4,5)P(3)--is highly expressed in mouse cerebellar Purkinje neurons and plays a role in motor coordination. We found that LTP evoked at parallel fibre synapses by 1 Hz stimulation or by NO donors was not sustained beyond 30 min when P-Rex was eliminated or Rac inhibited, suggesting that cerebellar LTP exhibits a late phase analogous to hippocampal LTP. In contrast, inhibition of PI3 kinase activity eliminated LTP at the induction stage.Our data suggest that a PI3K/P-Rex/Rac pathway is required for late phase LTP in the mouse cerebellum, and that other PI3K targets, which remain to be discovered, control LTP induction