VASE-Containing N-CAM Isoforms Are Increased in the Hippocampus in Bipolar Disorder but Not Schizophrenia

Abstract

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule that is involved in cellular migration, synaptic plasticity, and CNS development. In schizophrenia, a 105- to 115-kDa N-CAM protein is increased in CSF and in the hippocampus and prefrontal cortex. The variable alternatively spliced exon (VASE) of N-CAM is developmentally regulated and can be spliced into any of the major 120-, 140-, and 180-kDa N-CAM isoforms. We determined that the variable alternative spliced exon of N-CAM (VASE) also is increased in bipolar disorder by quantitative Western immunoblot. VASE immunoreactive proteins (triplet bands around 140 kDa and a single band around 145 kDa) were identified in soluble and membrane brain extracts and quantified in the hippocampus. Soluble VASE 140 kDa was increased in the hippocampus of patients with bipolar disorder as compared to controls, patients with schizophrenia, and suicide cases. Membrane-extracted VASE 140 and 145 kDa were unchanged in the same groups. Multiple 145-kDa VASE-immunoreactive proteins that also reacted to an N-CAM antibody were separated by isoelectric focusing and electrophoresis followed by western immunoblotting; however, the VASE 140-kDa proteins were only weakly N-CAM immunoreactive. By immunohistochemistry, VASE colocalized with GFAP-positive astrocytes in the hippocampus. VASE immunostaining was also observed in the cytoplasm of CA4 pyramidal neurons that were positive for phosphorylated high molecular weight neurofilament and synaptophysin terminals. Thus no differences in VASE were found in patients with schizophrenia, but there was a marked increase of VASE immunoreactive proteins in bipolar disorder. It is possible that abnormal regulation of N-CAM proteins results in differing patterns of abnormal expression in neuropsychiatric disorders.

Linkage disequilibrium mapping of bipolar affective disorder at 12q23‐q24 provides evidence for association at CUX2 and FLJ32356

“…Cux2, a potential regulator of neural cell adhesion molecule expression, [Quaggin et al, 1996;Jacobsen et al, 2001a] is an excellent neurobiological candidate gene with possible relevance in neuropsychiatric disorders [Vawter et al, 1998]. Although we failed to find evidence for mutations of major effect in the coding sequence of CUX2 in a previous study conducted on a smaller sample [Jacobsen et al, 2001a], the current LD findings suggest that we should not dismiss the possibility that susceptibility variants exist elsewhere in the gene.…”

Alterations of hippocampal secreted N-CAM in bipolar disorder and synaptophysin in schizophrenia

“…We have reported another abnormality in bipolar patients (summary in Table 2) involving the variable alternative spliced N-CAM exon, VASE N-CAM 145 kDa and 140 kDa. 28 Thus, different combinations of N-CAM isoforms are found in the brain of patients with schizophrenia and bipolar disorder relative to controls ( Table 2).…”

“…The N-CAM containing VASE isoform was found to be increased in the hippocampus and prefrontal cortex of bipolar patients, but not in patients with schizophrenia. 28 The SEC N-CAM isoform is produced by the incorporation of an alternative exon resulting in premature termination of transcription. 29 The possibility that the prior findings of increased N-CAM in bipolar disorder and schizophrenia 24,25,27,28 were related to abnormal production of the secreted (SEC) form of N-CAM was investigated.…”

To Model a Psychiatric Disorder in Animals Schizophrenia As a Reality Test

“…a Vawter et al 1998;Barbeau et al 1995;Impagnatiello et al 1998;Fatemi et al 1999. b Ohnuma et al 1998Eastwood et al 1995.…”