Alterations in the motor neuron-renshaw cell circuit in the Sod1G93A mouse model

Hanna Wootz, Eileen Fitzsimons-Kantamneni, Martin Larhammar, Travis M. Rotterman, Anders Enjin, Kalicharan Patra, Elodie André, Brigitte Van Zundert, Klas Kullander, Francisco J. Alvarez

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these cells during disease progression in the Sod1G93A mouse model. Most calbindin-immunoreactive (IR) Renshaw cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing.

Original languageEnglish
Pages (from-to)1449-1469
Number of pages21
JournalJournal of Comparative Neurology
Volume521
Issue number7
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Amyotrophic lateral sclerosis
  • Recurrent inhibition
  • Synapses
  • VAChT

ASJC Scopus subject areas

  • Neuroscience(all)

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