title: Neurophysiologische Charakterisierung von adulten vulnerablen und resistenten Motoneuronen in einem Mausmodell der Amyotrophen Lateralsklerose
title: Neurophysiological characterization of adult vulnerable and resistant motoneurons in a mouse model of amyotrophic lateral sclerosis
Creators: name: Fuchs, Andrea
Publisher: name: Philipps-Universität Marburg
Year: 2012
Subjects: Amyotrophic lateral sclerosis
Patch-Clamp-Methode
Amyotrophe Lateralsklerose
SOD-1
Patch clamp
Calcium
Motoneuron
Medizin, Gesundheit

description: Amyotrophic lateral sclerosis
      (ALS) is a neurodegenerative disease that affects motoneurons
      (MN) of the motor cortex, the brainstem and the spinal cord
      and leads to paralysis and atrophy of the innervated muscles.
      Patients mostly die within three to five years after symptom
      onset. There is no curative therapy. Overexcitability,
      calcium overload and mitochondrial disturbances are discussed
      as a common final cause of MN degeneration in this
      multifactorial disease. Because of technicals difficulties,
      so far excitability and calcium dynamics could only be
      analyzed in mouse models of ALS on a single cell level up to
      a postnatal age of ten days (P10), when mice did not show any
      symptoms. However, to study the direct mechanisms of
      neurodegeneration and to develop new therapies, analyses of
      MN during the stage of degeneration are essential. Here, for
      the first time a characterization of adult MN in acute
      brainstem slices of the SOD1-G93A ALS mouse model was
      performed using whole-cell patch-clamp measurements and
      fluorometric fura-2 calcium-imaging. The properties of the
      highly vulnerable hypoglossal MN were compared in wildtype
      and SOD1-G93A mice during disease endstage. The higher
      excitability and the increased persistent sodium inward
      currents, published for P10 SOD1-G93A mice, were not present
      in adult animals. Although electrophysiological properties
      were not prominently changed, the calcium clearance was
      significantly impaired in comparison to wildtype during
      disease endstage when MN were electrically stimulated to load
      them with high concentrations of calcium. However, with low
      physiological calcium load there were no differences. By
      comparing the vulnerable hMN with the resistant oculomotor
      MN, it was observed that the clearance deficit was specific
      for hMN and thereby is an explanation for the differential
      vulnerability. By fura-2 calcium-imaging in combination with
      mitochondrial uncoupling, specific pharmacological blocking
      of different calcium transporters and rhodamine123 imaging, a
      reduced calcium transport through the mitochondrial calcium
      uniporter was revealed as a cause for the impairment whereas
      the driving force for calcium into mitochondria was not
      changed. By blocking both the mitochondrial and the ER
      calcium uptake an increase of calcium transport by plasma
      membrane calcium transporters was indirectly shown in hMN of
      SOD1-G93A mice. From these result one can conclude that in
      the used ALS mouse model vulnerable MN try to compensate for
      a mitochondrial calcium uptake failure by upregulating plasma
      membrane calcium transport. However, with high calcium load
      during disease endstage this compensatory mechanism fails and
      a calcium overload might be the final cause of MN
      degeneration in ALS.
description: Die Amyotrophe Lateralsklerose
      (ALS) ist eine neurodegenerative Erkrankung, die Motoneurone
      (MN) von Kortex, Hirnstamm und Spinalmark betrifft. Folgen
      sind Lähmung der Muskulatur und der Tod des Patienten meist
      innerhalb von drei bis fünf Jahren nach Auftritt der ersten
      Symptome. Eine wirksame Therapie fehlt. Als gemeinsame finale
      Ursache der MN-Degeneration bei dieser multifaktoriellen
      Krankheit werden Übererregbarkeit der Neurone,
      Calciumüberladung und mitochondriale Schädigung diskutiert.
      Erregbarkeitseigenschaften und Calciumhomöostase der MN
      konnten in Mausmodellen der ALS auf Einzelzellebene aus
      technischen Gründen bisher nur in früh postnatalen
      (