Amyotrophic lateral sclerosis (ALS) is one of the most common motoneuron diseases. Although the etiology of ALS is still under debate, there is a growing consensus that axons and synapses are the first cellular sites of neurodegeneration. Using genetic (hSOD1G93A Tg mice) and pharmacological (iminodipropionitrile (IDPN)-injected mice) models of ALS, here we examined whether the impairment of axonal transport and synaptic environment might be involved in the early pathogenesis of ALS. Mutations in the copper/zinc SOD-1 gene, the first gene linked with ALS, result in the classical ALS phenotype. IDPN administration has been shown to produce dyskinetic syndrome via impairment of slow axonal transport. After immunohistochemical identification of the presynaptic terminals and glial processes surrounding the spinal motoneurons, we estimated the potential changes in somatic microenvironment by line profile analysis. Both in IDPN-injected mice and hSOD1G93A Tg mice at the early phase, the relative densities of synaptic contacts on the motoneuron cell bodies increased, while those of astrocytic contacts were declined. The contacts of microglial processes on motoneuron cell bodies were very few both in IDPN-injected mice and hSOD1G93A Tg mice at the early phase, and they were not affected until the late phase of disease of hSOD1G93A Tg mice. We then discriminated the glutamatergic and GABAergic synapses, and examined the changes in excitatory and inhibitory inputs into motoneurons. Our preliminary experiments also show that similar changes (increase in excitatory inputs and decrease in inhibitory inputs) occurred in IDPN-injected mice and hSOD1G93A Tg mice at the early phase. Considering the similar somatic environmental changes seen in IDPN-injected mice and hSOD1G93A Tg mice at the early phase, we hypothesize that the impairment of axonal transport may be involved in the onset of ALS. Now, we are going to determine the candidate molecules linking axonal transport impairment and changes in somatic microenvironment.