title: Transgenic mice overexpressing the extracellular domain of NCAM are impaired in working memory and cortical plasticity.
abstract: The neural cell adhesion molecule, NCAM, is a pivotal regulator of neural development, with key roles in axonal and dendritic growth and synaptic plasticity. Alterations in NCAM expression or proteolytic cleavage have been linked to human neuropsychiatric disorders such as schizophrenia, bipolar disorder and Alzheimer's disease, and may contribute to cognitive dysfunction. We have generated mice overexpressing the NCAM extracellular (EC) proteolytic cleavage fragment which has been reported to be increased in schizophrenic versus normal brains. These mice show impaired GABAergic innervation and reduced number of apical dendritic spines on pyramidal neurons in the prefrontal cortex (PFC). Here, these NCAM-EC transgenic mice were subjected to behavioral tasks and electrophysiological measurements to determine the impact of structural abnormalities in the PFC on synaptic and cognitive functions. NCAM-EC mice exhibited impaired working memory in a delayed non-match-to-sample task, which requires PFC function, but showed no differences in anxiety, olfactory abilities, or sociability. Transgenic mice displayed impaired long- and short-term potentiation in the PFC but normal synaptic plasticity in the hippocampus, suggesting that the abnormal synaptic innervation in NCAM-EC mice impairs PFC plasticity and alters working memory. These findings may have implications for cognitive dysfunctions observed in neuropsychiatric disorders.
authors.affiliation: Department of Biochemistry and Biophysics, UNC Schizophrenia Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Leann H
authors.initials: LH
authors.lastname: Brennaman
authors.forename: Gaga
authors.initials: G
authors.lastname: Kochlamazashvili
authors.forename: Luminita
authors.initials: L
authors.lastname: Stoenica
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Nonneman
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Moy
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Maness
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology* / Q000502:physiology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009924:Organ Culture Techniques; D017434:Protein Structure, Tertiary / Q000235:genetics; D059748:Proteolysis
chemical_list: D019006:Neural Cell Adhesion Molecules