University of Tasmania, Australia

Amyotrophic lateral sclerosis (ALS), the commonest phenotype of motor neuron disease, is a neurodegenerative disease resulting in dysfunction and subsequent degeneration of both upper (primarily neocortical) and lower (spinal ventral horn) motor neurons. The initial cause of this degeneration is still unknown, particularly for the 95% of those diagnosed with apparently sporadic disease, despite the identification of several different mutant proteins associated with familial disease. It is clear that although the clinical outcomes of the disease are defined by motor neuron degeneration, the disease is non-cell autonomous, involving other neuronal and non-neuronal populations. Although the roles of various non-neuronal cells in ALS pathogenesis have been investigated, relatively few studies have focused on interneurons. This is surprising since excitotoxicity has been implicated as a key pathological feature in ALS and there is strong clinical evidence, in both cortical and spinal regions, as well as histological and electrophysiological evidence from human cases and mouse models, to implicate reduced inhibitory neuronal influences in the pathogenesis of ALS. In this study we are completing a comprehensive pathological study of interneuronal changes in human ALS tissue in comparison to commonly used mouse models of ALS. This study is novel in that it will examine both affected and non-affected regions of well characterized human cases. In addition we are using cell culture techniques to test the hypothesis that interneuron dysfunction can by a primary disease causing mechanism in ALS.