One of the leading hypotheses for motoneuron degeneration in ALS is excitotoxicity, in which excessive calcium entry leads to cell death. Most work on excitotoxicity has focused on ligand-gated channels activated by the excitatory neurotransmitter glutamate. In contrast, this proposal focuses on the possibility that ALS alters voltage-gated channels and thus alters the intrinsic excitability of the motoneuron. We have shown that a specific type of sodium (Na+) channel is markedly elevated in motoneurons cultured from a transgenic mouse model of ALS (the SOD1 model). This current is NaP, the persistent component of the total Na+ current generating the action potential. NaP is a major factor controlling the number of action potentials per time generated in response to a given amount of synaptic input. Because each action potential allows calcium to enter the cell, elevated NaP in ALS motoneurons could play a major role in excitotoxic death. The goals of this proposal are to investigate mechanisms of the aberrant upregulation of NaP in mutant SOD1 motoneurons and to assess how drugs that change NaP influence motoneuron survival. Studies are carried out in culture, in vitro in a slice preparation, and in vivo in the intact animal, all using the mutant SOD1 mouse.
Aim 1 considers the issue of whether molecular subtypes or densities of the Na channels themselves change.
Aim 2 focuses on potential changes in the regulation of NaP in response to acute and chronic drug administration. The monoamines serotonin and norepinephrine enhance NaP and likely play a particularly important role in its normal regulation.
In Aim 3, the effects of NaP-specific drugs studied in aim 2 are evaluated for their effect on motoneuron survival both in culture and in the intact mouse. A key question addressed by Aims 2 and 3 is whether the monoamines further increase NaP above its already high levels in mutant SOD1 motoneurons. If so, then standard anti-depressant drugs may actually exacerbate motoneuron degeneration.
In Aim 4, we evaluate whether, as predicted from our cell culture work, NaP is upregulated at a very early stage in life. Presence of enhanced NaP in very young animals would indicate that this aberrant property may play a significant role in the disease onset. These studies will play an essential role in determining if NaP makes an important contribution to motoneuron degeneration in ALS. Moreover, the results may prove invaluable in establishing new therapeutic strategies ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS051462-01
Application #
6908533
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Refolo, Lorenzo
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$331,630
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Heckman, C J; Enoka, Roger M (2012) Motor unit. Compr Physiol 2:2629-82
Manuel, Marin; Heckman, C J (2011) Adult mouse motor units develop almost all of their force in the subprimary range: a new all-or-none strategy for force recruitment? J Neurosci 31:15188-94
Manuel, Marin; Heckman, C J (2011) Stronger is not always better: could a bodybuilding dietary supplement lead to ALS? Exp Neurol 228:5-8
Elbasiouny, Sherif M; Amendola, Julien; Durand, Jacques et al. (2010) Evidence from computer simulations for alterations in the membrane biophysical properties and dendritic processing of synaptic inputs in mutant superoxide dismutase-1 motoneurons. J Neurosci 30:5544-58
ElBasiouny, S M; Schuster, J E; Heckman, C J (2010) Persistent inward currents in spinal motoneurons: important for normal function but potentially harmful after spinal cord injury and in amyotrophic lateral sclerosis. Clin Neurophysiol 121:1669-79
Manuel, Marin; Iglesias, Caroline; Donnet, Maud et al. (2009) Fast kinetics, high-frequency oscillations, and subprimary firing range in adult mouse spinal motoneurons. J Neurosci 29:11246-56
Jiang, Mingchen; Schuster, Jenna E; Fu, Ronggen et al. (2009) Progressive changes in synaptic inputs to motoneurons in adult sacral spinal cord of a mouse model of amyotrophic lateral sclerosis. J Neurosci 29:15031-8
Heckman, C J; Mottram, Carol; Quinlan, Kathy et al. (2009) Motoneuron excitability: the importance of neuromodulatory inputs. Clin Neurophysiol 120:2040-54
Heckman, C J; Johnson, Michael; Mottram, Carol et al. (2008) Persistent inward currents in spinal motoneurons and their influence on human motoneuron firing patterns. Neuroscientist 14:264-75