Painless progressive mononeuritis multiplex secondary to AML associated neuroleukemiosis.

Neuroleukemiosis describes peripheral nerve involvement secondary to leukemic infiltration, a rare complication of leukemia with various clinical presentations, leading to diagnostic challenges for hematologists and neurologists. We present two cases of painless progressive mononeuritis multiplex secondary to neuroleukemiosis. A literature review of previously reported cases of neuroleukemiosis was undertaken. Neuroleukemiosis may present as a progressive mononeuritis multiplex. The diagnosis of neuroleukemiosis requires a high index of suspicion and be aided by repeated CSF analysis.

The intrinsic plasticity of medial vestibular nucleus neurons during vestibular compensation-a systematic review and meta-analysis.

BACKGROUND: Vestibular compensation is a homeostatic process that occurs in the central nervous system in response to peripheral vestibular dysfunction. Experimental studies in rodent models have suggested that unilateral peripheral vestibular lesions are correlated with an increase in the intrinsic excitability of central vestibular neurons. This process may be dependent on the intrinsic properties of the neurons themselves. We aimed to conduct a systematic review of the literature to survey the evidence for changes in intrinsic plasticity observed during the acute phase of vestibular compensation. METHODS: We systematically reviewed the literature regarding the electrophysiological effect of experimentally induced unilateral vestibular deafferentation (UVD) on the intrinsic membrane properties of medial vestibular nucleus neurons in animal models. We developed tools to assess the methodological quality (precision, validity and bias) of studies that met pre-determined inclusion and exclusion criteria. We extracted numerical data and performed a meta-analysis of specific quantitative data pooled from these studies. RESULTS: We identified 17 studies that satisfied the inclusion criteria. There is moderate quality evidence to suggest a statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, the spontaneous discharge rate increases by 4 spikes/s on average and the sensitivity to current stimuli increases. CONCLUSION: Using this novel approach, we demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental animal studies with similar aims.

Vestibular Interactions in the Thalamus.

It has long been known that the vast majority of all information en route to the cerebral cortex must first pass through the thalamus. The long held view that the thalamus serves as a simple hi fidelity relay station for sensory information to the cortex, however, has over recent years been dispelled. Indeed, multiple projections from the vestibular nuclei to thalamic nuclei (including the ventrobasal nuclei, and the geniculate bodies)- regions typically associated with other modalities- have been described. Further, some thalamic neurons have been shown to respond to stimuli presented from across sensory modalities. For example, neurons in the rat anterodorsal and laterodorsal nuclei of the thalamus respond to visual, vestibular, proprioceptive and somatosensory stimuli and integrate this information to compute heading within the environment. Together, these findings imply that the thalamus serves crucial integrative functions, at least in regard to vestibular processing, beyond that imparted by a "simple" relay. In this mini review we outline the vestibular inputs to the thalamus and provide some clinical context for vestibular interactions in the thalamus. We then focus on how vestibular inputs interact with other sensory systems and discuss the multisensory integration properties of the thalamus.

Efferent Vestibular Neurons Show Homogenous Discharge Output But Heterogeneous Synaptic Input Profile In Vitro.

Despite the importance of our sense of balance we still know remarkably little about the central control of the peripheral balance system. While previous work has shown that activation of the efferent vestibular system results in modulation of afferent vestibular neuron discharge, the intrinsic and synaptic properties of efferent neurons themselves are largely unknown. Here we substantiate the location of the efferent vestibular nucleus (EVN) in the mouse, before characterizing the input and output properties of EVN neurons in vitro. We made transverse serial sections through the brainstem of 4-week-old mice, and performed immunohistochemistry for calcitonin gene-related peptide (CGRP) and choline acetyltransferase (ChAT), both expressed in the EVN of other species. We also injected fluorogold into the posterior canal and retrogradely labelled neurons in the EVN of ChAT:: tdTomato mice expressing tdTomato in all cholinergic neurons. As expected the EVN lies dorsolateral to the genu of the facial nerve (CNVII). We then made whole-cell current-, and voltage-clamp recordings from visually identified EVN neurons. In current-clamp, EVN neurons display a homogeneous discharge pattern. This is characterized by a high frequency burst of action potentials at the onset of a depolarizing stimulus and the offset of a hyperpolarizing stimulus that is mediated by T-type calcium channels. In voltage-clamp, EVN neurons receive either exclusively excitatory or inhibitory inputs, or a combination of both. Despite this heterogeneous mixture of inputs, we show that synaptic inputs onto EVN neurons are predominantly excitatory. Together these findings suggest that the inputs onto EVN neurons, and more specifically the origin of these inputs may underlie EVN neuron function.

Noise normalizes firing output of mouse lateral geniculate nucleus neurons.

The output of individual neurons is dependent on both synaptic and intrinsic membrane properties. While it is clear that the response of an individual neuron can be facilitated or inhibited based on the summation of its constituent synaptic inputs, it is not clear whether subthreshold activity, (e.g. synaptic "noise"--fluctuations that do not change the mean membrane potential) also serve a function in the control of neuronal output. Here we studied this by making whole-cell patch-clamp recordings from 29 mouse thalamocortical relay (TC) neurons. For each neuron we measured neuronal gain in response to either injection of current noise, or activation of the metabotropic glutamate receptor-mediated cortical feedback network (synaptic noise). As expected, injection of current noise via the recording pipette induces shifts in neuronal gain that are dependent on the amplitude of current noise, such that larger shifts in gain are observed in response to larger amplitude noise injections. Importantly we show that shifts in neuronal gain are also dependent on the intrinsic sensitivity of the neuron tested, such that the gain of intrinsically sensitive neurons is attenuated divisively in response to current noise, while the gain of insensitive neurons is facilitated multiplicatively by injection of current noise- effectively normalizing the output of the dLGN as a whole. In contrast, when the cortical feedback network was activated, only multiplicative gain changes were observed. These network activation-dependent changes were associated with reductions in the slow afterhyperpolarization (sAHP), and were mediated at least in part, by T-type calcium channels. Together, this suggests that TC neurons have the machinery necessary to compute multiple output solutions to a given set of stimuli depending on the current level of network stimulation.

Intrinsic neuronal excitability: implications for health and disease.

The output of a single neuron depends on both synaptic connectivity and intrinsic membrane properties. Changes in both synaptic and intrinsic membrane properties have been observed during homeostatic processes (e.g., vestibular compensation) as well as in several central nervous system (CNS) disorders. Although changes in synaptic properties have been extensively studied, particularly with regard to learning and memory, the contribution of intrinsic membrane properties to either physiological or pathological processes is much less clear. Recent research, however, has shown that alterations in the number, location or properties of voltage- and ligand-gated ion channels can underlie both normal and abnormal physiology, and that these changes arise via a diverse suite of molecular substrates. The literature reviewed here shows that changes in intrinsic neuronal excitability (presumably in concert with synaptic plasticity) can fundamentally modify the output of neurons, and that these modifications can subserve both homeostatic mechanisms and the pathogenesis of CNS disorders including epilepsy, migraine, and chronic pain.

Calretinin: modulator of neuronal excitability.

Calretinin is a member of the calcium-binding protein EF-hand family first identified in the retina. As with the other 200-plus calcium-binding proteins, calretinin serves a range of cellular functions including intracellular calcium buffering, messenger targeting, and is involved in processes such as cell cycle arrest, and apoptosis. Calcium-binding proteins including calretinin are expressed differentially in neuronal subpopulations throughout the vertebrate and invertebrate nervous system and their expression has been used to selectively target specific cell types and isolate neuronal networks. More recent experiments have revealed that calretinin plays a crucial role in the modulation of intrinsic neuronal excitability and the induction of long-term potentiation (LTP). Furthermore, selective knockout of calretinin in mice produces disturbances of motor coordination and suggests a putative role for calretinin in the maintenance of calcium dynamics underlying motor adaptation.

Charge state of the fast gate in chloride channels: insights from electrostatic calculations in a schematic model.

Fast gating is a unique property of chloride channels, where a permeating Cl(-) ion acts as its own ligand in opening the channel. The glutamate residue implicated in fast gating normally carries a unit negative charge. Whether this charge needs to be protonated to enable permeation of a Cl(-) ion is an important question that will affect how models of chloride channels are constructed. We investigate the energetic consequences of the charge state of this glutamate residue from continuum electrostatics using a schematic cylindrical channel model. Both analytical solutions of the Poisson equation for an infinite cylinder and numerical ones for a finite cylinder are employed in the calculations.