Abstract
Amyotrophic lateral sclerosis (ALS) is a disease where upper and lower motor neurons die, and it is often associated with mutations of superoxide dismutase 1 (SOD1). We have used mouse models to compare physiologic and morphologic characteristics of cervical motor neurons in wild-type and mutant animals. Slices of the cervical spinal cord were prepared from old wild-type and mutant G93A and G85R mice, and intracellular recordings of membrane potential, resistance and responses to application of excitatory neurotransmitters were studied. Some motor neurons were injected with Lucifer Yellow for morphological analysis. There were no significant differences between membrane potential in the SOD1 mutants and aged wild-type mice, but membrane resistance was somewhat higher in the mutant motor neurons. Dendrites of the mutant motor neurons were not responsive to ionophoretic application of excitatory amino acids, although the cell body responded strongly. In Lucifer-filled cells, the dendrites were found to disappear. Mutant motor neurons were sometimes spontaneously active. Responses of mutant motor neurons to perfused glutamate with varying calcium concentrations in the Ringer’s solution were different from those of the wild-type cells.
Highlights
In 1869, French neurologist, Jean-Martin Charcot discovered a disease in humans characterized by abnormalities and loss of skeletal muscle mass and named it amyotrophic-related lateral sclerosis (ALS) [1]
There were no significant differences between membrane potential in the superoxide dismutase 1 (SOD1) mutants and aged wild-type mice, but membrane resistance was somewhat higher in the mutant motor neurons
The mutant motor neurons are very responsive to AMPA and kainic acid (KA) even at a lower concentration. These results show that the cell body still has electrical excitability and has excitatory amino acid receptors, even though the dendritic function of SOD1 mutant mouse has been very much reduced
Summary
In 1869, French neurologist, Jean-Martin Charcot discovered a disease in humans characterized by abnormalities and loss of skeletal muscle mass and named it amyotrophic-related lateral sclerosis (ALS) [1]. Mutations of superoxide dismutase 1 (SOD1) have been seen in about 20% of familial cases and 3% of sporadic cases [3, 4]. There are several different glutamate receptors (AMPA, kainic acid and NMDA), but the AMPA receptor is the one responsible for usual synaptic transmission This receptor usually consists of four subunits, GluA1, GluA2 GluA3 and GluA4), and the open ion channel is not permeable to calcium [11]. Kwak and Kawahara (2005) have shown both in mice and humans that ALS is associated with abnormal editing of GluA2 and have provided support for the hypothesis that the motor neuronal cell death is due to elevation in calcium concentration [12, 13]. We have performed electrophysiologic and morphologic studies comparing wild-type cervical motor neurons to those of SOD1 mutant mice in order to investigate changes occurring in structure, membrane biophysical properties and responses to excitatory amino acid neurotransmitters during the period in which motor neurons are showing injury
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