ALTERED CALCIUM HOMEOSTASIS AND ULTRASTRUCTURE IN MOTONEURONS OF MICECAUSED BY PASSIVELY TRANSFERRED ANTI-MOTONEURONAL IGG

Calcium homeostasis and ultrastructure are altered in motor axon termi nals (AT) of amyotrophic lateral sclerosis (ALS) patients and in mice injected with ALS IgG and exhibit increased density of synaptic vesicl es and increased intracellular calcium. To develop an immune-mediated passive transfer experimental model of both systemic weakness and alte red morphology, mice were inoculated intraperitoneally with anti-moton euronal Igc. Animals initially manifested muscle stiffness and evidenc e of autonomic cholinergic hyperactivity. Electron microscopic cytoche mistry within 12 hours (h) demonstrated significantly increased densit y of synaptic vesicles and calcium both in axon terminals of neuromusc ular junctions and synaptic boutons on spinal motoneurons. After 24 h the mice were severely weak and premorbid. The number of synaptic vesi cles was still larger than normal, but calcium was depleted from axon terminals and synaptic boutons. The motoneuron perikarya demonstrated the dilatation of the Golgi system and the rough endoplasmic reticulum with an increased amount of calcium. The NMDA receptor antagonist, MK -801, and the L-type calcium channel antagonist, Diltiazem, prevented clinical symptoms and some morphological alterations. These data demon strate that high titer anti-motoneuronal Ige can induce severe weaknes s and produce similar ultrastructural features of motor axon terminals in human ALS and in mice injected with ALS IgG, and support a key rol e for calcium in selective vulnerability of motoneurons.