Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses

Synaptic vesicle (SV) exocytosis mediating neurotransmitter release occurs spontaneously at low intraterminal calcium concentrations and is stimulated by a rise in intracellular calcium. Exocytosis is compensated for by the reformation of vesicles at plasma membrane and endosomes. Although the adaptor complex AP-3 was proposed to be involved in the formation of SVs from endosomes, whether its function has an indirect effect on exocytosis remains unknown. Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses. Presynaptic targeting of the tetanus neurotoxin-resistant vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is lost in mocha hippocampal MF terminals, whereas the localization of synaptobrevin 2 is unaffected. In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose. We conclude that lack of AP-3 results in more constitutive secretion and loss of an asynchronous evoked release component, suggesting an important function of AP-3 in regulating SV exocytosis at MF terminals

Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets

Antibody delivery to the CNS remains a huge hurdle for the clinical application of antibodies targeting a CNS antigen. The blood-brain barrier and blood-CSF barrier restrict access of therapeutic antibodies to their CNS targets in a major way. The very high amounts of therapeutic antibodies that are administered systemically in recent clinical trials to reach CNS targets are barely viable cost-wise for broad, routine applications. Though global CNS delivery of antibodies can be achieved by intrathecal application, these procedures are invasive. A non-invasive method to bring antibodies into the CNS reliably and reproducibly remains an important unmet need in neurology. In the present study, we show that intranasal application of a mouse monoclonal antibody against the neurite growth-inhibiting and plasticity-restricting membrane protein Nogo-A leads to a rapid transfer of significant amounts of antibody to the brain and spinal cord in intact adult rats. Daily intranasal application for 2 wk of anti-Nogo-A antibody enhanced growth and compensatory sprouting of corticofugal projections and functional recovery in rats after large unilateral cortical strokes. These findings are a starting point for clinical translation for a less invasive route of application of therapeutic antibodies to CNS targets for many neurological indications

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability

Matched Filters, Mate Choice and the Evolution of Sexually Selected Traits

Background Fundamental for understanding the evolution of communication systems is both the variation in a signal and how this affects the behavior of receivers, as well as variation in preference functions of receivers, and how this affects the variability of the signal. However, individual differences in female preference functions and their proximate causation have rarely been studied. Methodology/Principal Findings Calling songs of male field crickets represent secondary sexual characters and are subject to sexual selection by female choice. Following predictions from the “matched filter hypothesis” we studied the tuning of an identified interneuron in a field cricket, known for its function in phonotaxis, and correlated this with the preference of the same females in two-choice trials. Females vary in their neuronal frequency tuning, which strongly predicts the preference in a choice situation between two songs differing in carrier frequency. A second “matched filter” exists in directional hearing, where reliable cues for sound localization occur only in a narrow frequency range. There is a strong correlation between the directional tuning and the behavioural preference in no-choice tests. This second “matched filter” also varies widely in females, and surprisingly, differs on average by 400 Hz from the neuronal frequency tuning. Conclusions/Significance Our findings on the mismatch of the two “matched filters” would suggest that the difference in these two filters appears to be caused by their evolutionary history, and the different trade-offs which exist between sound emission, transmission and detection, as well as directional hearing under specific ecological settings. The mismatched filter situation may ultimately explain the maintenance of considerable variation in the carrier frequency of the male signal despite stabilizing selection

ПАТОЛОГИЯ, ВЫЗВАННАЯ ИМПЛАНТАТОМ: АЛГОРИТМ ОПРЕДЕЛЕНИЯ ЧАСТИЦ ПРИ ГИСТОПАТОЛОГИЧЕСКОМ ИССЛЕДОВАНИИ СИНОВИАЛЬНО-ПОДОБНОЙ ОКОЛОПРОТЕЗНОЙ мембраны (SLIM)

In histopathologic SLIM diagnostic (synovial-like interface membrane, SLIM) apart from diagnosing periprosthetic infection particle identification has an important role to play. The differences in particle pathogenesis and variability of materials in endoprosthetics explain the particle heterogeneity that hampers the diagnostic identification of particles. For this reason, a histopathological particle algorithm has been developed. With minimal methodical complexity this histopathological particle algorithm offers a guide to prosthesis material-particle identification. Light microscopic-morphological as well as enzyme-histochemical characteristics and polarization-optical proporties have set and particles are defined by size (microparticles, macroparticles and supra- macroparticles) and definitely characterized in accordance with a dichotomous principle. Based on these criteria, identification and validation of the particles was carried out in 120 joint endoprosthesis pathological cases. A histopathological particle score (HPS) is proposed that summarizes the most important information for the orthopedist, material scientist and histopathologist concerning particle identification in the SLIM.Важную роль при гистопатологическом исследовании синовиально-подобной околопротезной мембраны (SLIM), наряду с диагностикой околопротезной инфекции, играет идентификация частиц. Различия в патогенезе частиц и разнообразии материалов для эндопротезирования объясняют ту гетерогенность, которая затрудняет диагностическую идентификацию частиц. По этой причине был разработан гистопатологический алгоритм диагностики частиц, который при минимальных методологических сложностях обеспечивает идентификацию частиц материала протеза. Простые микроскопически-морфологические и энзим-гистохимические характеристики, а также поляризационно-оптические свойства позволяют определить размер частиц (микрочастицы, макрочастицы и супер-макрочастицы) и характеризовать их по дихотомическому принципу. На основании этих критериев были выполнены идентификация и аттестация частиц в 120 случаях патологической реакции на эндопротез сустава. Предложена гистопатологическая шкала частиц (HPS), которая суммирует важнейшую информацию для ортопедов, материаловедов и гистопатологов, касающуюся идентификации частиц методом SLIM

MicroRNA132 Modulates Short-Term Synaptic Plasticity but Not Basal Release Probability in Hippocampal Neurons

MicroRNAs play important regulatory roles in a broad range of cellular processes including neuronal morphology and long-term synaptic plasticity. MicroRNA-132 (miR132) is a CREB-regulated miRNA that is induced by neuronal activity and neurotrophins, and plays a role in regulating neuronal morphology and cellular excitability. Little is known about the effects of miR132 expression on synaptic function. Here we show that overexpression of miR132 increases the paired-pulse ratio and decreases synaptic depression in cultured mouse hippocampal neurons without affecting the initial probability of neurotransmitter release, the calcium sensitivity of release, the amplitude of excitatory postsynaptic currents or the size of the readily releasable pool of synaptic vesicles. These findings are the first to demonstrate that microRNAs can regulate short-term plasticity in neurons

Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord

Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord

Geometric, kinematic, and erosional history of the central Andean Plateau, Bolivia (15–17°S)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95425/1/tect1910.pd

Thermochronometer record of central Andean Plateau growth, Bolivia (19.5°S)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94850/1/tect1973.pd