Systemic Neurochemical Alterations in Schizophrenic Brain: Glutamate Metabolism in Focus

Abstract

We have used a systemic approach to establish a relationship between enzyme measures of glial glutamate and energy metabolism (glutamine synthetase and glutamine synthetase-like protein, glutamate dehydrogenase isoenzymes, brain isoform creatine phosphokinase) and two major glial proteins (glial fibrillary acidic protein and myelin basic protein) in autopsied brain samples taken from patients with schizophrenia (SCH) and mentally healthy subjects (23 and 22 cases, respectively). These biochemical parameters were measured in tissue extracts in three brain areas (prefrontal cortex, caudate nucleus, and cerebellum). Significant differences in the level of at least one of the glutamate metabolizing enzymes were observed between two studied groups in all studied brain areas. Different patterns of correlative links between the biochemical parameters were found in healthy and schizophrenic brains. These findings give a new perspective to our understanding of the impaired regulation of enzyme levels in the brain in SCH.

Multiple Forms of Glutamate Dehydrogenase in Animals: Structural Determinants and Physiological Implications

“…Elevated GDH levels were found in prefrontal cortex of schizophrenic patients, along with decreased levels of glutamine synthase [185,186]. According to the “glutamate hypothesis”, this may result in hypofunctioning of glutamatergic signaling leading to schizophrenia development.…”

Behavioral sequelae of astrocyte dysfunction: focus on animal models of schizophrenia

“…Besides GFAP, altered expression of the factors involved in glutamate (GLU) metabolism (e.g., glial glutamate transporter (GLT-1), glutamine synthetase, glutaminase and serine racemase) was found (Matute et al, 2005; Burbaeva et al, 2003, 2007; Bruneau et al, 2005; Toro et al, 2006; Seffek et al, 2006; 2008). In addition, up-regulation of an inducible isoform of heme oxygenase (HMOX1), that is restricted to glial cells and oxidizes cellular heme to biliverdin, carbon monoxide (CO), and free ferrous iron (Schipper, 2004), was found in the prefrontal cortex (PFC) of patients with schizophrenia (Prabakaran et al, 2004).…”

Comparative study of glutamate dehydrogenase in the brain of patients with schizophrenia and mentally healthy people

“…Определение количества форм ГДГ I, II и III проводили с помощью кроличьих антисывороток, полученных в лаборатории нейрохимии Научного центра психического здоровья [15], и вторичных ослиных антител к IgG кролика -F(ab')2-fragment NA9340 («Amersham Biosciences», Швеция), конъюгированных с пероксидазой хрена, в рабочем разведении 1:10 000. Специфичность антисывороток была оценена ECL-Вестерн-иммуноблоттингом с использованием очищенных образцов белков ГДГ, выделенных из мозга человека.…”

“…Исследование разнообразия форм ГДГ в мозге представляет особый интерес, так как дисфункции глутаматергических путей играют роль в развитии различных форм клинической патологии -болезни Альцгеймера [12], болезни Гентингтона [6,10,13], инсульта, эпилепсии, шизофрении [14,15] и депрессии [16].…”

“…Они могут либо представлять собой продукты разных генов, либо синтезироваться с разных видов мРНК, образованной путем альтернативного сплайсинга, или возникать вследствие посттрансляционных модификаций. Ранее при сравнении количества этих форм ГДГ в аутопсийных образцах мозга (лобная кора, хвостатое ядро и кора мозжечка) от больных шизофренией и психически здоровых мы обнаружили [15] достоверные различия.…”