Further studies on ectopic dendrite growth and other geometrical distortions of neurons in feline GMl gangliosidosis

Systematic Golgi studies have been performed on major subcortical, diencephalic, brain stem and spinal cord regions from cats with the inherited neuronal storage disease, GM1 gangliosidosis. Resulting data have been compared with other Golgi studies of neuronal storage disorders in man and animals, including an earlier, more limited examination of this same disease model. These previous studies have shown that in human and feline gangliosidoses cortical pyramidal neurons undergo remarkable changes in soma-dendritic geometry. The latter include the formation of conspicuous cellular enlargements between somata and axonal initial segments (meganeurites) and the sprouting of secondary neuritic processes from this same region of the cell. Further, ultrastructural studies have revealed normal appearing synapses on the surface of this ectopically placed dendritic-like membrane. Results of the present study indicate that the distribution of meganeurites, secondary neurites and other geometrical distortions of neurons in GM1 gangliosidosis varies with cell type and brain region. This cell type-specific response to the metabolic error and subsequent storage could be categorized in three ways. Firstly, certain types of cells (e.g. multipolar neurons of the amygdala and claustrum) exhibited changes similar to those reported for cortical pyramidal neurons. That is, cells of these regions either displayed spine or neurite-bearing meganeurites, or enlarged axon hillocks which were covered with similar processes. Other types of neurons did not demonstrate ectopic neurite growth or spine-covered meganeurites, but did display prominent aspiny meganeurites (e.g. neurons of the superior colliculus, periaqueductal gray, hypothalamus and basal forebrain nuclei). A third category of neurons did not possess meganeurites or neurite growth but instead demonstrated massive somatic expansion which exceeded that observed in meganeurite-bearing cell types (e.g. certain brain stem and spinal cord neurons). These data have been compared with the more limited Golgi studies of other types of neuronal storage disorders and the same types of neurons appeared to respond in similar fashion across this spectrum of diseases. The data presented and discussed in this paper demonstrate three significant morphological events which occur in neurons as a result of lysosomal hydrolase deficiency. These are (i) storage, which occurs in all neurons but manifests as meganeurite formation or somatic enlargement depending on the cell type, (ii) axon hillock or meganeurite-associated spine and neurite growth, and (iii) new synapse formation on spine-covered meganeurites and on neurites. The independent occurrence of meganeurites and neurites is not consistent with the view that these morphological changes are simply different manifestations of a single defect in the regulation of neuronal surface membrane production, as has been suggested previously. Rather, this study offers the view that axon hillock neurites and meganeurite-associated neurites and spines are the morphological hallmark of increased axon hillock-asociated synapse formation, whereas meganeurites themselves simply manifest the storage process. Possible factors controlling the expression of these features of neurons are discussed.