title: Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model.
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 Sod1(G93A) 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. J. Comp. Neurol. 521:1449-1469, 2013. © 2012 Wiley Periodicals, Inc.
authors.affiliation: Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Wootz
authors.forename: Eileen
authors.initials: E
authors.lastname: Fitzsimons-Kantamneni
authors.forename: Martin
authors.initials: M
authors.lastname: Larhammar
authors.forename: Travis M
authors.initials: TM
authors.lastname: Rotterman
authors.forename: Anders
authors.initials: A
authors.lastname: Enjin
authors.forename: Kalicharan
authors.initials: K
authors.lastname: Patra
authors.forename: Elodie
authors.initials: E
authors.lastname: André
authors.forename: Brigitte
authors.initials: B
authors.lastname: Van Zundert
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Alvarez