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

• Type of Material: Article
• Authors: Hanna Wootz, Uppsala University; Eileen FitzSimons-Kantamneni, Wright State University; Martin Larhammar, Uppsala University; Travis M. Rotterman, Emory University; Anders Enjin, Uppsala University; Kalicharan Patra, Uppsala University; Elodie Andre, Uppsala University; Brigitte van Zundert, Massachusetts Institute of Technology; Klas Kullander, Uppsala University; Francisco Alvarez, Emory University
• Language: English
• Date: 2013-05-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Wiley Periodicals, Inc.
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/cne.23266/abstract
• Title of Journal or Parent Work: Journal of Comparative Neurology
• ISSN: 0021-9967
• Volume: 521
• Issue: 7
• Start Page: 1449
• End Page: 1469
• Grant/Funding Information: Grant sponsors: This work was supported by grants from the NIHgrant NS NS047357 (FJA); The ALS Therapy Alliance-CVS Pharmacy (B.v.Z); Swedish Research Council – Medicine and Health; the foundations of Goran Gustafsson, A. Wiberg, Ahlen and Hedlund; Uppsala University; the Swedish Brain Foundation; and the Swedish Society for Medical Research (H.W.). K.K. is a Royal Swedish Academy of Sciences Research Fellow supported by a grant from the Knut and Alice Wallenberg Foundation.
• Keywords: recurrent inhibition; synapses; Amyotrophic Lateral Sclerosis; VAChT
• Research Categories: Biology, Neuroscience; Biology, Physiology

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 Chrna2 , cholinergic nicotinic receptor subunit alpha2), two general markers for motor neurons (NeuN and VAChT, vesicular acethylcholine transporter ) and two markers for fast motor neurons (Chondrolectin and Calca, calcitonin-related polypeptide alpha), 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 a diminished control of motor neuron firing.