Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior

Pillai-Nair, N., Panicker, A. K., Rodriguiz, R. M., Gilmore, K. L., Demyanenko, G. P., Huang, J. Z., Wetsel, W. C., Maness, P. F. (May 2005) Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. Journal of Neuroscience, 25 (18). pp. 4659-4671. ISSN 0270-6474

DOI: 10.1523/JNEUROSCI.0565-05.2005


The extracellular region of the transmembrane neural cell adhesion molecule (NCAM-EC) is shed as a soluble fragment at elevated levels in the schizophrenic brain. A novel transgenic mouse line was generated to identify consequences on cortical development and function of expressing soluble NCAM-EC from the neuron-specific enolase promoter in the developing and mature neocortex and hippocampus. NCAM-EC transgenic mice exhibited a striking reduction in synaptic puncta of GABAergic interneurons in the cingulate, frontal association cortex, and amygdala but not hippocampus, as shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65), GAD67, and GABA transporter 1. Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations of interneurons included basket interneurons evident in NCAM-EC transgenic mice intercrossed with a reporter line expressing green fluorescent protein and by parvalbumin staining. In addition, there appeared to be a reduction in excitatory synapses, as revealed by synaptophysin staining and apical dendritic spine density of cortical pyramidal cells. Behavioral analyses demonstrated higher basal locomotor activity of NCAM-EC mice and enhanced responses to amphetamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine maleate compared with wild-type controls. Transgenic mice were deficient in prepulse inhibition, which was restored by clozapine but not by haloperidol. Additionally, NCAM-EC mice were impaired in contextual and cued fear conditioning. These results suggested that elevated shedding of NCAM perturbs synaptic connectivity of GABAergic interneurons and produces abnormal behaviors that may be relevant to schizophrenia and other neuropsychiatric disorders.

Item Type: Paper
Uncontrolled Keywords: neural cell adhesion molecule NCAM interneuron GABAergic cingulate prepulse inhibition schizophrenia long term potentiation null mutant mice glutamic acid decarboxylylase Messenger RNA expression monkey prefrontal cortex n-cam visual cortex axon terminals knockout mice repulse inhibition
Subjects: diseases & disorders > mental disorders > schizophrenia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA dynamics
CSHL Authors:
Communities: CSHL labs > Huang lab
Depositing User: CSHL Librarian
Date: May 2005
Date Deposited: 09 Jan 2012 14:50
Last Modified: 10 May 2013 18:43
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