Dysregulation of glutamate carboxypeptidase II in psychiatric disease

Abstract

Experimental evidence is beginning to converge on an important role for dysregulation of glutamate carboxypeptidase II (GCPII) in schizophrenia. The goal of this study was to determine GCPII levels in postmortem brain specimens of patients with schizophrenia, bipolar disorder or unipolar depression and age-matched control subjects. We used, a high-affinity radioligand for GCPII, to probe for GCPII expression in prefrontal cortex (PFC) and mesial temporal lobe, two brain regions implicated in the pathophysiology of schizophrenia. We found that GCPII levels measured by [ 125 I]DCIT quantitative autoradiography were significantly lower in the PFC and entorhinal cortex in patients with schizophrenia compared to age-matched controls. Patients with bipolar disorder also expressed significantly lower GCPII levels in PFC than controls. The decrease in [ 125 I]DCIT binding in schizophrenia and bipolar disorder remained significant after adjusting for drug abuse. A significant difference in GCPII levels were also observed between schizophrenia relative to bipolar disorder and depressed subjects in the hippocampus-stratum lucidum and between schizophrenia and bipolar in the CA2 region of the hippocampus with bipolar and depressed subjects expressing higher levels of GCPII than subjects with schizophrenia. These differences in hippocampal GCPII levels may implicate differences in the etiologies of these mental disorders. In summary, this study demonstrates a regional dysregulation of GCPII expression in the brain of patients with schizophrenia and other

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

“…Other studies have demonstrated changes in gene expression patterns in BA9 in psychiatric disorders (Digney et al, 2005;Veldic et al, 2005;Guilarte et al, 2008). Within BA9, we detected diminished VGF in layer VI.…”

“…CA2 is an important information processing point between the dentate gyrus and the subiculum (Heckers et al, 2002). CA2 has also been implicated in psychiatric disorders (Benes et al, 2001;Knable et al, 2004;Dean et al, 2005), and, in particular, studies suggest a dysfunction of CA2 inhibitory GABAergic interneurons in severe mental illness (Müller et al, 2001;Tian et al, 2007;Guilarte et al, 2008). Our findings of reduced VGF expression in CA2 pyramidal cells of bipolar disorder patients suggest that, in addition to the alterations in inhibitory interneurons, there may be changes in the function of excitatory neurons.…”

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

“…Consistent with the hypothesis that GCPII regulates glutamate transmission, GCPII inhibitors have been shown to possess therapeutic utility in many preclinical models of neurodegenerative diseases with presumed underlying glutamate aberrations (Neale et al, 2005;Barinka et al, 2012). In addition, abnormal NAAG and GCPII levels have been detected in tissue samples from preclinical animal models and patients with neurodegenerative disorders, including amyotrophic lateral sclerosis (Tsai et al, 1991;Plaitakis and Constantakakis, 1993;Ghadge et al, 2003), epilepsy (Meyerhoff et al, 1992;Pacheco Otalora et al, 2007), schizophrenia (Ghose et al, 2004;Guilarte et al, 2008;Profaci et al, 2011), and Huntington's disease (Passani et al, 1997). Glutamate has also been widely implicated in pain perception, so consequently there has been interest in the development of potent orally available GCPII inhibitors as therapeutics for chronic pain states .…”

Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation

“…Protein expression and functionality of FOLH1 may therefore play an important role in the pathophysiology of psychiatric disorders. 151 It is possible that worse outcomes in patients with variant FOLH1 may be due to a GCPII functionality in the brain and its effect on the depressive symptoms rather than the FOLH1 effect on folate levels. So this is an encouraging observation that requires considerable further investigation.…”