The effects of neonatal basal forebrain lesions on cognition: towards understanding the developmental role of the cholinergic basal forebrain.

Abstract:  Abnormal development of the cholinergic basal forebrain has been implicated in numerous developmental disabilities such as Rett Syndrome and Down Syndrome. This review summarizes recent data using two rodent animal models that involve interrupting cholinergic basal forebrain projections on postnatal day 1 and postnatal day 7 when basal forebrain fibers are beginning to innervate their neocortical and hippocampal targets, respectively. In one model, electrolytic lesions in mice aimed at the basal forebrain on postnatal day 1 transiently reduce cholinergic markers in neocortex which induce permanent alterations in neocortical anatomy that correlate with impairments on cognitive tasks. Furthermore, the lesion effects are sex dependent. In another model, 192 IgG saporin lesions in rats on postnatal day 7 permanently reduce cholinergic markers in neocortex and hippocampus, and result in mild impairments in spatial processing, acquisition and exploratory activities. These data suggest that during the first postnatal week of development the cholinergic basal forebrain system is critical for normal neocortical differentiation and, possibly synaptogenesis in neural circuits that will be important for spatial memory and acquisition of spatial data. During the second postnatal week of development, the cholinergic basal forebrain system appears to take on a role largely similar to its adult role in selective attention and processing of new information. These studies also suggest strongly that interrupting cholinergic basal forebrain innervation of neocortex and hippocampus leads to anatomical and neurochemical abnormalities that may serve as neural substrates for some of the cognitive deficits seen in disorders such as Rett Syndrome and Down Syndrome.