PMID- 22634210
OWN - NLM
STAT- MEDLINE
DCOM- 20120918
LR  - 20131121
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 236
IP  - 2
DP  - 2012 Aug
TI  - Neural precursors (NPCs) from adult L967Q mice display early commitment to "in 
      vitro" neuronal differentiation and hyperexcitability.
PG  - 307-18
LID - 10.1016/j.expneurol.2012.05.010 [doi]
AB  - The pathogenic factors leading to selective degeneration of motoneurons in ALS 
      are not yet understood. However, altered functionality of voltage-dependent Na(+) 
      channels may play a role since cortical hyperexcitability was described in ALS 
      patients and riluzole, the only drug approved to treat ALS, seems to decrease 
      glutamate release via blockade or inactivation of voltage-dependent Na(+) 
      channels. The wobbler mouse, a murine model of motoneuron degeneration, shares 
      some of the clinical features of human ALS. At early stages of the wobbler 
      disease, increased cortical hyperexcitability was observed. Moreover, riluzole 
      reduced motoneuron loss and muscular atrophy in treated wobbler mice. Here, we 
      focussed our attention on specific electrophysiological properties, like 
      voltage-activated Na(+) currents and underlying regenerative electrical activity, 
      as read-outs of the neuronal maturation process of neural stem/progenitor cells 
      (NPCs) isolated from the subventricular zone (SVZ) of adult early symptomatic 
      wobbler mice. In self-renewal conditions, the rate of wobbler NPC proliferation 
      "in vitro" was 30% lower than that of healthy mice. Conversely, the number of 
      wobbler NPCs displaying early neuronal commitment and action potentials was 
      significantly higher. Upon switching from proliferative to differentiative 
      conditions, NPCs underwent significant changes in the key properties of voltage 
      gated Na(+) currents. The most notable finding, in cells with neuronal 
      morphology, was an increase in Na(+) current density that strictly correlated 
      with an increased probability to generate action potentials. This feature was 
      remarkably more pronounced in neurons differentiated from wobbler NPCs that upon 
      sustained stimulation, displayed short trains of pathological facilitation. In 
      agreement with this result, an increase in the number of c-Fos positive cells, a 
      surrogate marker of neuronal network activation, was observed in the mesial 
      cortex of the wobbler mice "in situ". Thus these findings, all together, suggest 
      that a state of early neuronal hyperexcitability may be a major contributor of 
      motoneuron vulnerability.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - DiFebo, Francesca
AU  - DiFebo F
AD  - Department of Biology and Biotechnology L. Spallanzani, University of Pavia, 
      Pavia, Italy.
FAU - Curti, Daniela
AU  - Curti D
FAU - Botti, Francesca
AU  - Botti F
FAU - Biella, Gerardo
AU  - Biella G
FAU - Bigini, Paolo
AU  - Bigini P
FAU - Mennini, Tiziana
AU  - Mennini T
FAU - Toselli, Mauro
AU  - Toselli M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120522
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Sodium Channels)
RN  - 0RH81L854J (Glutamine)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Action Potentials/*genetics
MH  - Age Factors
MH  - Amino Acid Substitution/genetics
MH  - Animals
MH  - Cell Differentiation/*genetics
MH  - Cell Survival/genetics
MH  - Glutamine/genetics
MH  - Leucine/genetics
MH  - Mice
MH  - Mice, Neurologic Mutants
MH  - Neural Stem Cells/metabolism/*physiology
MH  - Neurogenesis/*genetics
MH  - Neurons/*physiology
MH  - Sodium Channels/genetics
EDAT- 2012/05/29 06:00
MHDA- 2012/09/19 06:00
CRDT- 2012/05/29 06:00
PHST- 2012/02/06 00:00 [received]
PHST- 2012/05/03 00:00 [revised]
PHST- 2012/05/09 00:00 [accepted]
PHST- 2012/05/29 06:00 [entrez]
PHST- 2012/05/29 06:00 [pubmed]
PHST- 2012/09/19 06:00 [medline]
AID - S0014-4886(12)00208-7 [pii]
AID - 10.1016/j.expneurol.2012.05.010 [doi]
PST - ppublish
SO  - Exp Neurol. 2012 Aug;236(2):307-18. doi: 10.1016/j.expneurol.2012.05.010. Epub 
      2012 May 22.