VASE-containing N-CAM isoforms are increased in the hippocampus in bipolardisorder but not schizophrenia

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule th at is involved in cellular migration, synaptic plasticity, and CNS developm ent. In schizophrenia, a 105- to 115-kDa N-CAM protein is increased in CSF and in the hippocampus and prefrontal cortex. The variable alternatively sp liced 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 increas ed in bipolar disorder by quantitative Western immunoblot. VASE immunoreact ive 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 p atients with bipolar disorder as compared to controls, patients with schizo phrenia, and suicide cases. Membrane-extracted VASE 140 and 145 kDa were un changed in the same groups. Multiple 145-kDa VASE-immunoreactive proteins t hat also reacted to are NCAM antibody were separated by isoelectric focusin g and electrophoresis followed by western immunoblotting; however, the VASE 140-kDa proteins were only weakly N-CAM immunoreactive. By immunohistochem istry, VASE colocalized with GFAP-positive astrocytes in the hippocampus. V ASE immunostaining was also observed in the cytoplasm of CA4 pyramidal neur ons that were positive for phosphorylated high molecular weight neurofilame nt and synaptophysin terminals. Thus no differences in VASE were found in p atients with schizophrenia, but there was a marked increase of VASE immunor eactive proteins in bipolar disorder. It is possible that abnormal regulati on of N-CAM proteins results in differing patterns of abnormal expression i n neuropsychiatric disorders.