Faculty Bibliography

Schwann cells are remarkably plastic cells that can both form and stably maintain myelin sheaths around axons and also rapidly dedifferentiate upon injury. New findings (Parkinson, D.B., A. Bhaskaran, P. Arthur-Farraj, L.A. Noon, A. Woodhoo, A.C. Lloyd, M.L. Feltri, L. Wrabetz, A. Behrens, R. Mirsky, and K.R. Jessen. 2008. J. Cell Biol. 181:625-637) indicate that the transition between these distinct states of differentiation is directed by the transcription factor Krox-20, which promotes and maintains myelination, and c-Jun, which antagonizes it. Cross-inhibition of these transcription factors serves to switch Schwann cells between the myelinated and dedifferentiated phenotypes, respectively

Filamentous inclusions composed of the microtubule-associated protein tau are found in Alzheimer disease and other tauopathic neurodegenerative diseases, but the mechanisms underlying their formation from full-length protein monomer under physiological conditions are unclear. To address this issue, the fibrillization of recombinant full-length four-repeat human tau was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods and a small-molecule inducer of aggregation, thiazine red. Data were then fit to a simple homogeneous nucleation model with rate constant constraints established from filament dissociation rate, critical concentration, and mass-per-unit length measurements. The model was then tested by comparing the predicted time-dependent evolution of length distributions to experimental data. Results indicated that once assembly-competent conformations were attained, the rate-limiting step in the fibrillization pathway was tau dimer formation. Filament elongation then proceeded by addition of tau monomers to nascent filament ends. Filaments isolated at reaction plateau contained approximately 2 tau protomers/beta-strand spacing on the basis of mass-per-unit length measurements. The model suggests four key steps in the aggregation pathway that must be surmounted for tau filaments to form in disease.

Accurate knowledge of the morphology of the human brain is required for minimally or non-invasive surgical interventions. On the (sub-)cellular level, brain tissue is generally characterized using optical microscopy, which allows extracting morphological features with a wide spectrum of staining procedures. The preparation of the histological slices, however, often leads to artifacts resulting in imperfect morphological data. In addition, the generation of 3D data is time-consuming. Therefore, we propose synchrotron radiation-based micro computed tomography (SRmicroCT) avoiding preparation artifacts and giving rise to the 3D morphology of features such as gray and white matter on the micrometer level. One can differentiate between white and gray matter without any staining procedure because of different X-ray absorption values. At the photon energy of 10keV, the white matter exhibits the absorption of 5.08 cm(-1), whereby the value for the gray matter corresponds to 5.25 cm(-1). The tomography data allow quantifying the local strains in the histological images using registration algorithms. The deformation of histological slices compared to the SRmicroCT in a 2D-2D registration leads to values of up to 6.3%. Mean deformation values for the Nissl-stained slices are determined to about 1%, whereas the myelin-stained slices yield slightly higher values than 2%

Previous studies have shown that VEGF expression in forebrain increases after experimental manipulations that increase neuronal activity. One question is whether this also occurs in motor neurons. If so, it could be potentially advantageous from a therapeutic perspective, because VEGF prevents motor neuron degeneration. Therefore, we asked whether endogenous VEGF expression in motor neurons could be modulated. We also asked how VEGF exposure would influence motor neurons using electrophysiology. Immunocytochemistry showed that motor neuron VEGF expression increased after a stimulus that increases neuronal and motor activity, i.e., convulsive seizures. The increase in VEGF immunoreactivity occurred in all motor neuron populations that were examined 24h later. This effect was unlikely to be due to seizure-induced toxicity, because silver degeneration stain did not show the typical appearance of a dying or dead neuron. To address the effects of VEGF on motor neuron function, VEGF was applied directly to motor neurons while recording intracellularly, using a brainstem slice preparation. Exposure to exogenous VEGF (200 ng/ml) in normal conditions depressed stimulus-evoked depolarization of hypoglossal motor neurons. There was no detectable effect of VEGF on membrane properties or firing behavior. We suggest that VEGF is upregulated in neurons when they are strongly activated, and VEGF depresses neuronal excitation as a compensatory mechanism. Failure of this mechanism may contribute to diseases that involve a dysregulation of VEGF, excessive excitation of motor neurons, and motor neuron loss, such as amyotrophic lateral sclerosis (ALS)

Significant outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (C for cellular), to a toxic and infectious form, PrP(Sc) (Sc for scrapie). None of the prionoses currently have an effective treatment. Some forms of prion disease are thought to be spread by oral ingestion of PrP(Sc), such as chronic wasting disease and variant Creutzfeldt-Jakob disease. Attempts to obtain an active immunization in wild-type animals have been hampered by auto-tolerance to PrP and potential toxicity. Previously, we demonstrated that it is possible to overcome tolerance and obtain a specific anti-PrP antibody response by oral inoculation of the PrP protein expressed in an attenuated Salmonella vector. This past study showed that 30% of vaccinated animals were free of disease more than 350 days post-challenge. In the current study we have both optimized the vaccination protocol and divided the vaccinated mice into low and high immune responder groups prior to oral challenge with PrP(Sc) scrapie strain 139A. These methodological refinements led to a significantly improved therapeutic response. 100% of mice with a high mucosal anti-PrP titer immunoglobulin (Ig) A and a high systemic IgG titer, prior to challenge, remained without symptoms of PrP infection at 400 days (log-rank test P<0.0001 versus sham controls). The brains from these surviving clinically asymptomatic mice were free of PrP(Sc) infection by Western blot and histological examination. These promising findings suggest that effective mucosal vaccination is a feasible and useful method for overcoming tolerance to PrP and preventing prion infection via an oral route

Glutamate (Glu) is associated with excitotoxic cell damage. Memantine modulates the glutamate induced excitotoxicity in Alzheimer's disease (AD). No information is available as to the influence of memantine on in vivo brain glutamate levels. Hippocampal Glu levels were measured in cognitively impaired and normal individuals (n=10) before and after 6 months of memantine treatment, using three dimensional high spatial resolution (0.5 cm(3) voxels) proton magnetic resonance spectroscopy at 3 T. These measurements were also repeated in a non-treated cognitively normal group (n=6). Treatment with memantine decreased Glu/Cr (creatine) ratio in the left hippocampal region. Memantine reduced hippocampal glutamate levels, which may be consistent with its anti-excitotoxic property

DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.

The human mirror neuron system is thought to be the underlying basis of perception-action coupling involved in imitation and action understanding. In order to examine this issue we examined the recruitment of the mirror neuron system, as reflected in mu rhythm suppression in a population of adults with Down syndrome (DS) with known strengths in imitation but with impairments in perceptual-motor coupling. Ten healthy adults and 10 age-matched adults with (DS) participated in the study. Subjects were asked to make self-paced movements (execution), and view movements made by the experimenter (observation). The action consisted of reaching with the dominant hand to grasp and lift a cup. Cortical responses were recorded with a whole head magnetoencephalography (MEG) system. Both groups demonstrated significant attenuation of the mu rhythm in bilateral sensorimotor areas when executing the action. Typical adults also demonstrated significant mu suppression in bilateral sensorimotor areas during observation of the action. In contrast, when observing the movement, adults with DS showed a significantly reduced overall attenuation of mu activity with a distinct laterality in the pattern of mu suppression. These results suggest that there is a dysfunction in the execution/observation matching system in adults with DS and has implications for the functional role of the human mirror neuron system.

Fast-spiking cells (FS cells) are a prominent subtype of neocortical GABAergic interneurons with important functional roles. Multiple FS cell properties are coordinated for rapid response. Here, we describe an FS cell feature that serves to gate the powerful inhibition produced by FS cell activity. We show that FS cells in layer 2/3 barrel cortex possess a dampening mechanism mediated by Kv1.1-containing potassium channels localized to the axon initial segment. These channels powerfully regulate action potential threshold and allow FS cells to respond preferentially to large inputs that are fast enough to 'outrun' Kv1 activation. In addition, Kv1.1 channel blockade converts the delay-type discharge pattern of FS cells to one of continuous fast spiking without influencing the high-frequency firing that defines FS cells. Thus, Kv1 channels provide a key counterbalance to the established rapid-response characteristics of FS cells, regulating excitability through a unique combination of electrophysiological properties and discrete subcellular localization

In this issue of Neuron, Ajemian et al. present a computational model of the activity of neurons in primary motor cortex (M1) during isometric movements in different postures. By modeling the output of M1 neurons in terms of their influence on muscles, they find each M1 neuron maps its output into a particular pattern of muscle actions