Progressive changes in synaptic inputs to motoneurons in adult sacral spinal cord of a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motoneurons. One potential mechanism is excitotoxicity. We studied the behaviors of spinal neurons using an in vitro preparation of the sacral cord from the G93A SOD1 mouse model of ALS. Measurements were conducted at presymptomatic [approximately postnatal day 50 (approximately P50)], early (approximately P90), and late (>P120) stages of the disease. Short-latency reflexes (SRs) in ventral roots, presumably monosynaptic, were evoked by electrical stimulation of a dorsal root. The fraction of motoneurons capable of responding to this activation was evaluated by measuring the compound action potential [total motor activity (TMA)] evoked by antidromic stimulation of the distal ventral root. In mutant SOD1 (mSOD1) mice, both the SR and the TMA decreased with age compared with nontransgenic littermates, ruling out the SR as a source of increasing excitotoxicity. Spinal interneuron activity was assessed using the synchronized ventral root bursts generated by both bath application of blockers of inhibitory neurotransmitters (glycine, GABA(A)) and agonists of glutamate receptors (especially NMDA receptors). After symptom onset, a higher percentage of preparations from mSOD1 mice exhibited bursting, and these bursts exhibited more sub-bursts and a more disorganized pattern. In mSOD1 mice with clear muscle tremor, the ventral roots exhibited spontaneous synchronized bursts, which were highly sensitive to the blockade of NMDA receptors. These data suggest that although short-latency sensory input does not increase as symptoms develop, interneuron activity does increase and may contribute to excitotoxicity.
Jiang
Mingchen
M
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. m-jiang@northwestern.edu
Schuster
Jenna E
JE
Fu
Ronggen
R
Siddique
Teepu
T
Heckman
C J
CJ
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001703:Biophysics / Q000379:methods; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D018450:Disease Progression; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007395:Interneurons / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology* / Q000502:physiology*; D009154:Mutation; D016202:N-Methylaspartate / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D011930:Reaction Time / Q000235:genetics; D012018:Reflex / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000473:pathology / Q000502:physiology*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; C000606290:SOD1 protein, human; C056723:FG 9041; D016202:N-Methylaspartate; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1