Neural Cell Adhesion Molecule Ablation in Mice Causes Hippocampal Dysplasia and Loss of Septal Cholinergic Neurons

The neural cell adhesion molecule (NCAM) is implicated in nervous system development and plasticity. In humans, abnormal NCAM expression has been linked to the pathogenesis of neuropsychiatric and neurodegenerative disorders accompanied by cognitive dysfunctions. Impaired cognition is also observed in NCAM-deficient (NCAM(-/-)) mice. Considering the importance of the septal cholinergic nuclei and the hippocampus for cognition, we performed quantitative morphological analyses of these areas in young and adult (2 and 13 months old, respectively) NCAM(-/-) mice and wild-type (NCAM(+/+)) littermates. In young mice, we found lower numbers of septal cholinergic neurons in NCAM(-/-) than in NCAM(+/+) mice. Despite deficient numbers of neurons, total lengths of cholinergic axons and choline acetyltransferase protein levels in the hippocampus of NCAM(-/-) mice were normal. The hippocampus of NCAM(-/-) mice was atrophic, notably in the CA3 subfield and the dentate gyrus (DG). The atrophy appeared to have different primary causes in the two subfields: loss of pyramidal cells in CA3 and reduced branching and volume of granule cell dendrites in the DG. The frequency of dendritic spines on dentate granule cells in NCAM(-/-) mice was normal. Numbers of parvalbumin-positive (PV+) interneurons were reduced in NCAM(-/-) mice in proportion to subfield volume loss, and the ratios of principal cells to PV+ interneurons were similar to those of NCAM(+/+) mice. None of the observed abnormalities was exaggerated or alleviated in adult NCAM(-/-) mice. Our observations indicate that NCAM ablation causes structural abnormalities in the hippocampus and the forebrain cholinergic system in adult mice, which may contribute to impaired cognition in NCAM(-/-) mice. J. Comp. Neurol. 519: 2475-2492, 2011. (C) 2011 Wiley-Liss, Inc.