Sodium channel endocytosis drives axon initial segment plasticity.

Activity-dependent plasticity of the axon initial segment (AIS) endows neurons with the ability to adapt action potential output to changes in network activity. Action potential initiation at the AIS highly depends on the clustering of voltage-gated sodium channels, but the molecular mechanisms regulating their plasticity remain largely unknown. Here, we developed genetic tools to label endogenous sodium channels and their scaffolding protein, to reveal their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons in slices and primary cultures.

Real-world challenges in the diagnosis of primary progressive multiple sclerosis.

Background And Purpose: Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real-world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria.

Methods: Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files.

The Phenotypic and Mutational Spectrum of the FHONDA Syndrome and Oculocutaneous Albinism: Similarities and Differences.

Purpose: The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to compare it to albinism.

Subjects And Methods: We retrospectively collected molecular, ophthalmic, and electrophysiological data of 28 patients molecularly confirmed with FHONDA from the Netherlands (9), Israel (13), France (2), and the United States of America (4). We compared the data to that of 133 Dutch patients with the 3 most common types of albinism in the Netherlands: oculocutaneous albinism type 1 (49), type 2 (41), and ocular albinism (43).

Topological Analysis of the Brainstem of the Australian Lungfish Neoceratodus forsteri.

This paper presents a survey of the cell masses in the brainstem of the Australian lungfish Neoceratodus forsteri, based ontransversely cut Bodian-stained serial sections, supplemented by immunohistochemical data from the recent literature. This study is intended to serve a double purpose. First it concludes and completes a series of publications on the structure of the brainstem in representative species of all groups of anamniote vertebrates.

Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice.

Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known.

Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex.

The axon initial segment (AIS) is a critical microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts in vivo as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using the mouse whisker-to-barrel pathway as a model system in combination with immunofluorescence, confocal analysis and electrophysiological recordings, we observed bidirectional AIS plasticity in cortical pyramidal neurons.

The effect of military training on the sense of agency and outcome processing.

Armed forces often rely on strict hierarchical organization, where people are required to follow orders. In two cross-sectional studies, we investigate whether or not working in a military context influences the sense of agency and outcome processing, and how different durations (junior cadets vs senior cadets) and types (cadets vs privates) of military experience may modulate these effects. Participants could administer painful electrical shocks to a 'victim' in exchange for money, either by their own free choice, or following orders of the experimenter.

Novel mutations in the PITX2 gene in Pakistani and Mexican families with Axenfeld-Rieger syndrome.

Purpose: Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder that affects the anterior segment of the eye. The aim of this study was to examine the PITX2 gene to identify possible novel mutations in Pakistani and Mexican families affected by the ARS phenotype.

Methods: Three unrelated probands with a diagnosis of ARS were recruited for this study.

Effective Deep Brain Stimulation for Obsessive-Compulsive Disorder Requires Clinical Expertise.

Background: Deep brain stimulation (DBS) is an innovative treatment for severe obsessive-compulsive disorder (OCD). Electrodes implanted in specific brain areas allow clinicians to directly modulate neural activity. DBS affects symptomatology in a completely different way than established forms of treatment for OCD, such as psychotherapy or medication.

Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues.

Background: ATP-binding cassette (ABC) transporters are involved in a huge range of physiological processes. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum, a metabolic disease with progressive soft tissue calcification.

Methods: The aim of the present study was to analyze gene expression levels of selected ABC transporters associated with cholesterol homeostasis in metabolic active tissues, such as the liver, kidney and white adipose tissue (WAT) of Abcc6 mice from an early and late disease stage (six-month-old and 12-month-old mice).

The Phenotypic Spectrum of Albinism.

Purpose: To describe the phenotypic spectrum of a large cohort of albino patients, to investigate the relationship between the ocular abnormalities and the visual acuity (VA), and to define diagnostic criteria for the white population. We also estimated the prevalence of albinism in The Netherlands.

Design: Retrospective cohort study.

Antiplatelet and Anticoagulant Drugs Do Not Affect Visual Outcome in Neovascular Age-Related Macular Degeneration in the BRAMD Trial.

Purpose: To determine if use of antiplatelet or anticoagulant (AP/AC) medication influences visual acuity in patients with active neovascular age-related macular degeneration (N-AMD).

Design: Retrospective analysis of data from a randomized controlled trial.

Methods: Setting: Multicenter.

Small Scale Production of Recombinant Adeno-Associated Viral Vectors for Gene Delivery to the Nervous System.

Adeno-associated viral vectors have numerous applications in neuroscience, including the study of gene function in health and disease, targeting of light-sensitive proteins to anatomically distinct sets of neurons to manipulate neuronal activity (optogenetics), and the delivery of fluorescent protein to study anatomical connectivity in the brain. Moreover several phase I/II clinical trials for gene therapy of eye and brain diseases with adeno-associated viral vectors have shown that these vectors are well tolerated by human patients. In this chapter we describe a detailed protocol for the small scale production of recombinant adeno-associated viral vectors.

Principles of Current Vertebrate Neuromorphology.

Causal analysis of molecular patterning at neural plate and early neural tube stages has shown that the central nervous system (CNS) of vertebrates is essentially organized into transverse neural segments or neuromeres and longitudinal zones which follow the curved axis of the brain. The intersection of the longitudinal and transverse patterning processes in the embryonic brain leads to the formation of a checkerboard pattern of distinct progenitor domains called "fundamental morphological units" (FMUs). The topologically invariant pattern formed by the ventricular surfaces of the FMUs of a given taxon represents the "Bauplan" or "blueprint" of the brain of that taxon.

Layer-specificity in the effects of attention and working memory on activity in primary visual cortex.

Neuronal activity in early visual cortex depends on attention shifts but the contribution to working memory has remained unclear. Here, we examine neuronal activity in the different layers of the primary visual cortex (V1) in an attention-demanding and a working memory task. A current-source density analysis reveales top-down inputs in the superficial layers and layer 5, and an increase in neuronal firing rates most pronounced in the superficial and deep layers and weaker in input layer 4.

LONG-TERM FOLLOW-UP OF PATIENTS WITH RETINITIS PIGMENTOSA TYPE 12 CAUSED BY CRB1 MUTATIONS: A Severe Phenotype With Considerable Interindividual Variability.

Purpose: To examine the long-term clinical course and variability in a large pedigree segregating CRB1 type autosomal recessive retinitis pigmentosa.

Methods: An observational case study of 30 patients with CRB1 type autosomal recessive retinitis pigmentosa, homozygous for the CRB1 c.3122T > C; p.

Comparing the Effectiveness of Bevacizumab to Ranibizumab in Patients with Exudative Age-Related Macular Degeneration. The BRAMD Study.

Purpose: To compare the effectiveness of bevacizumab and ranibizumab in the treatment of exudative age-related macular degeneration (AMD).

Design: Multicentre, randomized, controlled, double-masked clinical trial in 327 patients. The non-inferiority margin was 4 letters.

Loss of MAPK Pathway Activation in Post-Mitotic Retinal Cells as Mechanism in MEK Inhibition-Related Retinopathy in Cancer Patients.

Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.

Synaptic vesicle dynamic changes in a model of fragile X.

Background: Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs).