Susceptibility to seizure-induced injury and acquired microencephaly following intraventricular injection of saporin-conjugated 192 IgG in developing rat brain

Abstract

To study the role of neurotrophin-responsive neurons in brain growth and developmental resistance to seizure-induced injury, we infused saporin-conjugated 192-IgG (192 IgG-saporin), a monoclonal antibody directed at the P75 neurotrophin receptors (p75(NTR)), into the ventricles of postnatal day 8 (P8) rat pups. 7-10 days after immunotoxin treatment, loss of p75(NTR) immunoreactivity was associated with depletion of basal forebrain cholinergic projection to the neocortex and hippocampus. Kainic acid (KA)-induced seizures on P15 resulted in hippocampal neuronal injury in the majority of toxin-treated animals (13/16), but only rarely in saline-injected controls (2/25) (P < 0.001). In addition, widespread cerebral atrophy and a significant decrease in brain weight with preserved body weight were observed. Volumetric analysis of the hippocampal hilar region revealed a 2-fold reduction in perikaryal size and a 1.7-fold increase in cell packing density after 192 IgG-saporin injection. These observations indicate that neurotrophin-responsive neurons including basal forebrain magnocellular cholinergic neurons may be critical for normal brain growth and play a protective role in preventing excitotoxic neuronal injury during development.