Motor neurone acetylcholinesterase release precedes neurotoxicity caused by systemic administration of excitatory amino acids and strychnine

We have proposed that neuronal overactivation by either stimulation of exci tatory receptors or hypofunction of inhibitory circuits is a cause of exces sive acetylcholinesterase (AChE) release, which, in turn, can contribute to ALS/MND pathogenesis. We investigated histochemical and histopathological changes in cell populations of the mouse spinal ventral horn upon in vivo s timulation of glutamate receptors with L-aspartate (ASP, 10-50 mg/kg, intra peritoneal: i.p.), or blockade of glycine receptors with strychnine (STRY, 2 mg/kg, i.p.). ASP in P4-P13 (postnatal age in days) but not in older mice , and STRY irrespective of age, provoked rapid, striking depletions of moto r neurone AChE, and appearance of AChE activity in astrocytes. This was fol lowed by recovery of the enzyme in most motor neurones, astrocyte activatio n, and statistically significant changes in: brain macrophage infiltration, loss of interneurones and motor neurones and neuronophagic images includin g rosettes of glial cells surrounding a central 'ghost-like' motor neurone. Although AChE release preceded the neuropathology found, it is not known i f its uptake is a cause of glial activation. However, it has: been shown th at the enzyme potentiates non-N-metyl-D-aspartate receptors identical to th ose that mediate astrocyte activation. AChE activity produces protons and c holine, possible microglial activators. These are putative routes towards l ong-lasting neuropathology. (C) 1998 Elsevier Science B.V. All rights reser ved.