The ionic mechanisms underlying N-methyl-d-aspartate receptor-induced, tetrodotoxin-resistant membrane potential oscillations in lamprey neurons active during locomotion

Activation of N-methyl-d-aspartate (NMDA) receptors can induce tetrodotoxin (TTX)-resistant membrane potential oscillations as well as fictive locomotion in the in vitro preparation of the lamprey spinal cord. The ionic basis of these oscillations were investigated in the presence of N-methyl-d,l-aspartate and TTX. Addition of blocking agents (2-amino-5-phosphonovalerate and tetraethylammonium (TEA)) and selective removal or substitution of certain ions (Mg²⁺, Ca²⁺, Na⁺, Ba²⁺) were used in the analysis of the oscillations. The depolarizing phase of the oscillation requires Na⁺ ions but not Ca²⁺ ions. The depolarization becomes larger if TEA is administered in the bath, which presumably is due to a blockade of potassium (K⁺) channels activated during the depolarizing phase. The repolarization appears to depend on a Ca²⁺ entry, which presumably acts indirectly by an activation of Ca²⁺-dependent K⁺ channels. Together with the NMDA-induced voltage dependence, this will bring the membrane potential back down to a hyperpolarized level.     

The effect of current passage on N-methyl-D-aspartate-induced, tetrodotoxin-resistant membrane potential oscillations in lamprey neurons active during locomotion

In lamprey spinal cord neurons, N-methyl-aspartate (NMA) can elicit tetrodotoxin (TTX)-resistant membrane potential oscillations (10-25 mV), that are of similar frequency to those recorded during NMA-induced fictive locomotion before TTX. The frequency of the oscillations was progressively reduced when increasing the amount of hyperpolarizing DC current. Brief de- or hyperpolarizing pulses gave phase-dependent effects on the duration of the oscillation cycle and rhythm resetting. Periodic stimuli could entrain the oscillatory activity. Under normal conditions, these oscillations will be influenced by synaptic activity, leading to an adequate coordination between neurons active during locomotion.     

High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses

Synaptic plasticity involves remodeling of extracellular matrix. This is mediated, in part, by enzymes of the matrix metalloproteinase (MMP) family, in particular by gelatinase MMP-9. Accordingly, there is a need of developing methods to visualize gelatinolytic activity at the level of individual synapses, especially in the context of neurotransmitters receptors. Here we present a high-resolution fluorescent in situ zymography (ISZ), performed in thin sections of the alcohol-fixed and polyester wax-embedded brain tissue of the rat (Rattus norvegicus), which is superior to the current ISZ protocols. The method allows visualization of structural details up to the resolution-limit of light microscopy, in conjunction with immunofluorescent labeling. We used this technique to visualize and quantify gelatinolytic activity at the synapses in control and seizure-affected rat brain. In particular, we demonstrated, for the first time, frequent colocalization of gelatinase(s) with synaptic N-methyl-D-aspartic acid (NMDA)- and AMPA-type glutamate receptors. We believe that our method represents a valuable tool to study extracellular proteolytic processes at the synapses, it could be used, as well, to investigate proteinase involvement in a range of physiological and pathological phenomena in the nervous system.     

The neurodegenerative process in a neurotoxic rat model and in patients with Huntington's disease: histopathological parallels and differences

Although Huntington's disease (HD) occurs only in humans, the use of animal models is crucial for HD research. New genetic models may provide novel insights into HD pathogenesis, but their relevance to human HD is problematic, particularly owing to a lower number of typically degenerated and dying striatal neurons and consequent insignificant reactive gliosis. Hence, neurotoxin-induced animal models are widely used for histopathological studies. Unlike in humans, the neurodegenerative process (NDP) of the HD phenotype develops very fast after the application of quinolinic acid (QA). For that reason, we compared three groups of rats in more advanced stages (1–12 months) of the QA lesion with 3 representative HD cases of varying length and grade. The outcomes of our long-term histological study indicate that significant parallels may be drawn between HD autopsies and QA-lesioned rat brains (particularly between post-lesional months 3 and 9) in relation to (1) the progression of morphological changes related to the neuronal degeneration, primarily the rarefaction of neuropil affecting the density as well as the character of synapses, resulting in severe striatal atrophy and (2) the participation of oligodendrocytes in reparative gliosis. Conversely, the development and character of reactive astrogliosis is principally conditioned by the severity of striatal NDP in the context of neuron–glia relationship. Despite the above-described differences, morphological patterns in which the components of striatal parenchyma react to the progression of NDP are similar in both human and rat brains. Our study specifies the possibilities of interpreting the morphological findings gained from the QA-induced animal model of HD in relation to HD post-mortem specimens.     

Revisiting the astrocyte-oligodendrocyte relationship in the adult CNS

The lineages of both astrocytes and oligodendrocytes have been popular areas of research in the last decade. The source of these cells in the mature CNS is relevant to the study of the cellular response to CNS injury. A significant amount of evidence exists to suggest that resident precursor cells proliferate and differentiate into mature glial cells that facilitate tissue repair and recovery. Additionally, the re-entry of mature astrocytes into the cell cycle can also contribute to the pool of new astrocytes that are observed following CNS injury. In order to better understand the glial response to injury in the adult CNS we must revisit the astrocyte-oligodendrocyte relationship. Specifically, we argue that there is a common glial precursor cell from which astrocytes and oligodendrocytes differentiate and that the microenvironment surrounding the injury determines the fate of the stimulated precursor cell. Ideally, better understanding the origin of new glial cells in the injured CNS will facilitate the development of therapeutics targeted to alter the glial response in a beneficial way.     

Calcium-permeable acid-sensing ion channel in nociceptive plasticity: A new target for pain control

The development of chronic pain involves increased sensitivity of peripheral nociceptors and elevated neuronal activity in many regions of the central nervous system. Much of these changes are caused by the amplification of nociceptive signals resulting from the modulation and altered expression of specific ion channels and receptors in the central and peripheral nervous system. Understanding the processes by which these ion channels and receptors are regulated and how these mechanisms malfunction may lead to new treatments for chronic pain. Here we review the contribution of the Ca²⁺-permeable acid-sensing ion channel (ASIC_Ca) in the development and persistence of chronic pain, and the potential underlying mechanisms. Accumulating evidence suggests that ASIC_Ca represents an attractive new target for developing effective therapies for chronic pain.