Higher Gamma-Aminobutyric Acid Neuron Density in the White Matter of Orbital Frontal Cortex in Schizophrenia

Background: In the orbitofrontal cortex (OFC), reduced gray matter volume and reduced glutamic acid decarboxylase 67kDa isoform (GAD67) messenger (m) RNA are found in schizophrenia; however, how these alterations relate to developmental pathology of interneurons is unclear. The present study therefore aimed to determine if increased interstitial white matter neuron (IWMN) density exists in the OFC; whether gamma-aminobutyric acid (GABA) ergic neuron density in OFC white matter was altered; and how IWMN density may be related to an early-expressed inhibitory neuron marker, Dlx1, in OFC gray matter in schizophrenia. Methods: IWMN densities were determined (38 schizophrenia and 38 control subjects) for neuronal nuclear antigen (NeuN+) and 65/67 kDa isoform of glutamic acid decarboxylase immunopositive (GAD65/67+) neurons. In situ hybridization was performed to determine Dlx1 and GAD67 mRNA expression in the OFC gray matter. Results: NeuN and GAD65/67 immunopositive cell density was significantly increased in the superficial white matter in schizophrenia. Gray matter Dlx1 and GAD67 mRNA expression were reduced in schizophrenia. Dlx1 mRNA levels were negatively correlated with GAD65/67 IWMN density. Conclusions: Our study provides evidence that pathology of IWMNs in schizophrenia includes GABAergic interneurons and that increased IWMN density may be related to GABAergic deficits in the overlying gray matter. These findings provide evidence at the cellular level that the OFC is a site of pathology in schizophrenia and support the hypothesis that inappropriate migration of cortical inhibitory interneurons occurs in schizophrenia.