Neural Cell Adhesion Molecule-Secreting Transgenic Mice Display Abnormalities in GABAergic Interneurons and Alterations in Behavior

Abstract

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 (ϩ)-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.

Polysialylated Neural Cell Adhesion Molecule Is Involved in Induction of Long-Term Potentiation and Memory Acquisition and Consolidation in a Fear-Conditioning Paradigm

“…The present study draws an important parallel between conditions in humans and animals, showing that an excess of soluble PSA and PSA-NCAM in the hippocampus of wild-type mice leads to deficits in contextual memory. Furthermore, in agreement with our observations on PSA-NCAM-Fc injected in wild-type mice, transgenic mice that overexpress soluble NCAM under the control of the late acting neuron-specific enolase promoter also exhibit deficits in contextual fear conditioning (Pillai-Nair et al, 2005). These and our results strongly suggest that upregulation of soluble NCAM, with a yet-unknown extent of polysialylation, as found under pathological conditions may lead to cognitive deficits.…”

“…This paradigm has been chosen previously to show impairment in cued (amygdala-dependent) and contextual (hippocampus-and amygdala-dependent) fear memories in NCAM-deficient mice (Stork et al, 2000), in mice deficient for polysialyltransferase ST8SiaII/STX, which is important for polysialylation of NCAM during early phases of development (Angata et al, 2004), and in mice that transgenically secrete soluble extracellular NCAM fragments (Pillai-Nair et al, 2005).…”

Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters

“…1 D, available at www.jneurosci.org as supplemental material). Notably, evidence from animal models suggest that clozapine, in contrast to conventional antipsychotic drugs blocking D 2 receptors, selectively improves GABAergic circuitry functions in cerebral cortex (Pillai-Nair et al, 2005) possibly by enhancing inhibitory inputs onto pyramidal neurons through a network-based mechanism (Gao, 2007). In agreement with this hypothesis, clozapineregulated methylation of GABAergic chromatin, as reported here for the animal and human brain, requires functional brain circuitry, because Gad1-H3K4 methylation remains unaffected in neuronal cultures treated with clozapine (Huang and Akbarian, 2007).…”

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…As a group, CAM genes have also been associated with schizophrenia in a pathway analytical study (43). Transgenic mice lacking NRCAM isoforms show deficits in learning and long-term potentiation (LTP) in the hippocampus and in prepulse inhibition responses, whereas mice overexpressing the extracellular domain of NRCAM exhibit WM deficits and impaired plasticity in prefrontal regions (46,(50)(51)(52)(53).…”