Hippocampal mossy fiber sprouting and elevated trkB receptor expression following systemic administration of low dose domoic acid during neonatal development

Abstract

We have previously reported that serial systemic injections of low-dose (subconvulsive) domoic acid (DOM) during early postnatal development produces changes in both behavior and hippocampal cytoarchitecture in aged rats (17 months) that are similar to those seen in existing animal models of temporal lobe epilepsy. Herein we report further hippocampal changes, consisting of mossy fiber sprouting and associated changes in the trkB receptor population in young adult (3 months) rats, and further, report that these changes show regional variation throughout the septo-temporal axis of the hippocampus. Groups of Sprague Dawley rat pups were injected daily from postnatal day 8-14 with either saline (n = 23) or 20 microg/kg DOM (n = 25), tested for key indicators of neonatal neurobehavioral development, and then left undisturbed until approximately 90 days of age, at which time brain tissue was removed, hippocampi were dissected, fixed and processed using either Timm's stain to visualize hippocampal mossy fiber sprouting (MFS) or trkB immunohistochemistry to visualize full length trkB receptors. Multiple sections from dorsal, mid, and ventral hippocampus were analyzed separately and all measures were conducted using image analysis software. The results indicate significant increases in MFS in the inner molecular layer in treated animals with corresponding changes in trkB receptor density. Further we identified significant increases in trkB receptor density in the hilus of the dentate gyrus and area CA3 and report increased mossy fiber terminal density in the stratum lucidum in treated rats. The magnitude of these changes differed between sections from dorsal, mid, and ventral hippocampus. We conclude that low dose neonatal DOM produces cytoarchitectural changes indicative of abnormal development and/or synaptic plasticity that are progressive with age and show regional variation within the hippocampal formation.