Time course of hippocampal GABAergic interneurons and spatial learning in SOD1 (G93A) mice

Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, has been associated to cognitive deficits. To date, limited attention has been devoted to the hippocampus of SOD1 (G93A) mice, acknowledged model of ALS. We hypothesized possible association between cognitive deficits and changes of GABAergic system in the hippocampus. To study the hippocampal GABAergic system of SOD1 (G93A) mice we analyzed brain sections of transgenic animals before the onset of the clinical symptoms and at the terminal stage of the disease, as well as matching controls at comparable ages. Coronal brain sections were immunohistochemically processed to visualize the largest class of the hippocampal interneurons, the parvalbumin-immunopositive (PVi) GABAergic cells. After image acquisition, the hippocampus was reconstructed and analyzed with ImageJ. In SOD1 (G93A) mice of both groups the number of PVi neurons was reduced by one-third to two-thirds compared to controls. The decrease of PVi cells involved all hippocampal subregions. Interestingly, the PVi cell population was reduced already before the onset of the clinical symptoms. To investigate for possible behavioral outcome of this alteration, we performed an experiment of spatial learning to test hippocampal circuitry connected with cognitive performance. Mice underwent the Barnes Maze test. Briefly, each animal was put in the middle of a circular table with 20 small holes around the circumference. Only one led to a box in which the animal could hide. Indices of learning included latency to reach the box, number of incorrect holes explored, and length of the exploratory path. Once finished the analysis of Barnes Maze behavioral data, we will combine them with structural PVi data to find possible correlations between spatial learning performances and alterations of the hippocampal GABAergic circuitry. Our preliminary findings on PVi interneurons, though not yet correlated with behavioral data, well seem to support hippocampal circuitry as key initial point of the pathological chain of events, with potential implications on diagnosis and treatment of ALS.