Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats

We have shown previously that neonatal intraventricular injections of the selective cholinergic immunotoxin 192 IgG saporin on postnatal day 7 (pnd 7) induce marked cholinergic loss in hippocampus and neocortex and a learning impairment on pnd 15. In the present study, we analysed the behavioural, morphological and neurochemical effects of earlier intraventricular injection of the immunotoxin 192 IgG saporin (pnd 1 and 3). We hypothesised that these earlier lesions would interrupt a critical stage in neocortical maturation, and impair behavior more profoundly than the later lesions. Passive avoidance (PA) learning and locomotor activity during the PA test were assessed on pnd 15. Retention of the PA task was assessed on pnd 16. Reactivity to spatial and object novelty was assessed on pnd 180 in a spatial open field test with five objects. Choline acetyltransferase (ChAT) activity was measured in basal forebrain targets on pnd 20 and pnd 180. Neonatal administration of 192 IgG saporin resulted in a slower acquisition of the PA task in females; retention and locomotor activity were not affected. On pnd 180, reaction to spatial novelty was mildly impaired in lesioned rats of both sexes. There was a marked reduction of ChAT in the hippocampus and neocortex of lesioned rats of both sexes, at both ages. Morphological analysis of the somatosensory cortex of lesioned rats revealed alterations in cortical development with sex specific variations in total cortical thickness. These results suggest that interrupting cholinergic basal forebrain innervation of neocortex and hippocampus during the first postnatal days affects the development of cognitive behaviour, neurochemistry and cortical organisation in a sex specific manner. Furthermore, the alterations in cortical organization are more profound than those noted after a lesion later in postnatal development. These behavioural and morphological abnormalities could be considered a model for several neurodevelopmental disorders associated with mental retardation.