High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons.

Dendritic spikes function as cardinal components of rodent neocortical circuit computations. Recently, the biophysical properties of human pyramidal neurons (PNs) have been reported to be divergent, raising the question of whether dendritic spikes have homologous roles in the human neocortex. To directly address this, we made electrical recordings from the soma and apical dendrites of human and rat layer 2/3 PNs of the temporal cortex. In both species, dendritic excitatory input led to the initiation of sodium-channel-mediated dendritic spikes. Dendritic sodium spikes could be generated across a wide input range, exhibited a similar frequency range of activation, and forward-propagated with high-fidelity to implement stereotyped computations in human and rat PNs. However, the physical expansion and complexification of the apical dendritic trees of human PNs allowed the enriched expression of dendritic spike generation. The computational capacity of human PNs is therefore enhanced by the widespread implementation of a conserved dendritic integration mechanism.

Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease.

A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin (n-agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n-agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n-agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n-agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.

Subgaleal haemorrhage in the newborn: A call for early diagnosis and aggressive management.

Subgaleal haemorrhage (SGH) is an important cause of preventable morbidity and mortality in the neonate. Its increased prevalence in recent years has coincided with the rise in the number of births assisted by vacuum extraction. Three deaths in Australia within the last 7 years have been the subject of two coronial inquests. Subsequent coronial reports have highlighted that neonatal death from SGH can be prevented if appropriate attention is paid to identification of risk factors, early diagnosis, close observation and aggressive treatment. To prevent unnecessary deaths, all involved in the care of the baby after birth need to be aware of the importance of prompt diagnosis, monitoring and early treatment of SGH.

Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection. Part 2: theoretical, biochemical and practical aspects.

The importance of the extent of resection for gliomas, and the utility of aminolevulinic acid (ALA) and protoporphyrin IX fluorescence in increasing the extent of resection, has become increasingly evident over the past decade. This review continues from Part 1 and focuses on the biochemical mechanisms by which ALA ingestion leads to tumour fluorescence, and discusses practicalities of the equipment and techniques needed to introduce ALA and fluorescence guided resection into neurosurgical practice.

Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumour resection. Part 1: Clinical, radiological and pathological studies.

The intraoperative identification and resection of glioma is a significant and important challenge in neurosurgery. Complete resection of the enhancing tumour increases the median survival time in glioblastoma compared to partial glioma resection; however, it is achieved in fewer than half of eligible patients when conventional tumour identification methods are used. Increasing the incidence of complete resection, without causing excess morbidity, requires new methods to accurately identify neoplastic tissue intraoperatively, such as use of the drug 5-amino-levulinic acid (ALA). After ALA ingestion, the fluorescent molecule protoporphyrin IX (PpIX) accumulates in high grade glioma, allowing the neurosurgeon to more easily detect and accurately resect tumour. The utility of ALA has been demonstrated in a large, multicentre phase III randomised control trial of 243 patients with high grade glioma. ALA use led to a significant increase in the incidence of complete resection (65% compared to 36%), improved progression-free survival at 6 months (41% compared to 21%), fewer reinterventions, and delayed onset of neurological deterioration. This review provides a broad assessment of ALA-PpIX fluorescence-guided resection, with Part 1 focusing on its clinical efficacy, and correlations with imaging and histology. The theoretical, biochemical and practical aspects of ALA use are reviewed in Part 2.

Microglia modulate hippocampal neural precursor activity in response to exercise and aging.

Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX(3)CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blocking antibody against the CX(3)CL1 receptor, CX(3)CR1, but not control IgG, dramatically reduced the neurosphere formation frequency in mice that had exercised. While an increase in soluble CX(3)CL1 was observed following running, reduced levels of this chemokine were found in the aged brain. Lower levels of CX(3)CL1 with advancing age correlated with the natural decline in neural precursor cell activity, a state that could be partially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX(3)CL1-CX(3)CR1 axis critically contributes toward this process.

p75 neurotrophin receptor regulates basal and fluoxetine-stimulated hippocampal neurogenesis.

It is widely acknowledged that neurogenesis occurs in the adult hippocampus under normal conditions and that the rate can be regulated by environmental factors, including antidepressant drugs, with concomitant effects on behaviour. Using a quick and sensitive flow cytometry method that can assess changes in the number of bromodeoxyuridine (BrdU)-positive cells in hippocampus, in combination with traditional histological cell counts in the dentate gyrus, we report that mice lacking the p75 neurotrophin receptor gene (p75(NTR-/-)) have significantly reduced hippocampal neurogenesis. Chronic treatment with the antidepressant fluoxetine stimulated hippocampal cell proliferation in p75(NTR-/-) animals, but it did not result in an increase above basal levels of the number of newly born neurons in the dentate gyrus. These results indicate that p75(NTR) acts as a regulator of fluoxetine-stimulated as well as basal adult hippocampal neurogenesis.

The p75 neurotrophin receptor regulates hippocampal neurogenesis and related behaviours.

Although changes to neural circuitry are believed to underlie behavioural characteristics mediated by the hippocampus, the contribution of neurogenesis to this process remains controversial. This is partially because the molecular regulators of neurogenesis remain to be fully elucidated, and experiments generically preventing neurogenesis have, for the most part, depended on paradigms involving irradiation. Here we show that mice lacking the p75 neurotrophin receptor (p75(NTR-/-)) have 25% fewer neuroblasts and 50% fewer newborn neurons in the dentate gyrus, coincident with increased rates of cell death of newly born cells and a significantly smaller granular cell layer and dentate gyrus, than those of p75(NTR+/+) mice. Whereas p75(NTR-/-) mice had increased latency to feed in a novelty-suppressed feeding paradigm they had increased mobility in another test of "depression", the tail-suspension test. p75(NTR-/-) mice also had subtle behavioural impairment in Morris water maze tasks compared to wild-type animals. No difference between genotypes was found in relation to anxiety or exploration behaviour based on the elevated-plus maze, light-dark, hole-board, T-maze or forced-swim tests. Overall, this study demonstrates that p75(NTR) is an important regulator of hippocampal neurogenesis, with concomitant effects on associated behaviours. However, the behavioural attributes of the p75(NTR-/-) mice may be better explained by altered circuitry driven by the loss of p75(NTR) in the basal forebrain, rather than direct changes to neurogenesis.