Brief reportGene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients
Introduction
Mood disorders are common and have serious consequences. The lifetime prevalence of major depressive disorder (MDD) is estimated to be 16% (Kessler et al., 2003). Neuropsychological, functional neuroimaging and morphological studies indicate that the prefrontal cortex (PFC) is involved in the pathogenesis of depression. A number of studies show that hypofunction of the PFC correlates with disease severity in both MDD and bipolar disorder (BD) (Drevets et al., 2008, Price and Drevets, 2010, Swaab et al., 2000): for example, a strongly altered glucose metabolism was found in the dorsolateral PFC (DLPFC) and anterior cingulated cortex (ACC) (Price and Drevets, 2010). Moreover, BD patients exhibit pronounced impairment of a number of tasks mediated by the PFC (Zihl et al., 1998). In addition, a reduction of grey matter volume was found in the DLPFC in both mood disorders, accompanied by reductions in density and size of neurons and glial cells (Price and Drevets, 2010, Rajkowska et al., 1999, Rajkowska et al., 2001).
Gamma-aminobutyric acid (GABA) and l-glutamic acid (glutamate) are two major neurotransmitters that may affect PFC activity in depression (Hashimoto, 2011, Krystal et al., 2002, Sanacora and Saricicek, 2007). In living patients, an increased glutamate content was reported in BD in both ACC and DLPFC (Frye et al., 2007, Lan et al., 2009), whereas prefrontal GABA and glutamate/glutamine concentrations were either reduced or unchanged in MDD patients (Hasler et al., 2007, Walter et al., 2009). A reduced density of GABAergic neurons was found in the postmortem ACC of BD patients and in the DLPFC of MDD patients (Cotter et al., 2002, Rajkowska et al., 2007). Furthermore, the transcript levels of a number of GABA subunits were decreased in the PFC of depressed suicide victims (Merali et al., 2004). For the glutamate pathway, reduced gene expression of NMDA receptor subunits (NR1 and NR2A) was found in the DLPFC of depressed patients (Beneyto and Meador-Woodruff, 2008). Furthermore, a microarray study showed dysregulation of genes related to the GABA and glutamate pathways in the ACC and DLPFC (Choudary et al., 2005).
However, it should be noted that in the postmortem studies data on the major changes in the GABAergic and glutamatergic systems in depression (Gao and Bao, 2010) were mainly obtained in younger suicidal patients. Therefore, the present study aimed to study GABA and glutamate pathway changes in non-suicidal elderly depressed patients. We used real-time quantitative PCR (qPCR) on isolated grey matter of the ACC and DLPFC in order to compare the expression of components of the GABAergic and glutamatergic pathways in mood disorder patients and matched controls.
Section snippets
Subjects
Brain samples were collected by the Netherlands Brain Bank (NBB), after written informed consent from the patient or their next of kin for a brain autopsy and the use of the material and medical records for research purposes. The depressed patients had been diagnosed in psychiatric clinics either as MDD or BD during their lifetime according to the DSM-III, DSM-IIIR or DSM-IV criteria, and the diagnosis was confirmed on the basis of the DSM-IV criteria by a board-certified psychiatrist using the
Results
In the ACC, no significant difference between MDD and BD patients was found for the GABAergic pathway markers, with the exception of GABRB1, which showed a trend toward a significant decrease in MDD compared to BD (values of 0.01 < P ≤ 0.05 are considered to be a trend). The data from MDD and BD were subsequently pooled for further analysis. GABRB2 transcript levels were decreased in the pooled depression group compared to the matched controls (Table 2). In the DLPFC, no difference in GABA related
Discussion
We observed alterations in the GABAergic and glutamatergic pathways in the PFC in depression. A significant decrease in transcript levels of two genes was found, i.e. of GABRB2, one of the subunits of the GABAA receptor, and of PSD-95, a scaffold protein related to the glutamatergic pathway, which indicates diminished activity in these pathways in depression. These alterations were only present in the ACC and not in the DLPFC. The possible confounders – age, CSF-pH and PMD – did not affect our
Role of funding source
Dr. A-M Bao is supported by Nature Science Foundation of China (30970928) and The Science and Technology Program of Zhejiang Province, China (2009C34020); Dr. A-M Bao and Prof. Dick F. Swaab were supported by the China Exchange Program of the Royal Netherlands Academy of Arts and Sciences (KNAW) (project 10CDP037); Ms Juan Zhao is supported by the China State Scholar Fund (2008694007) and China Exchange Program of the Royal Netherlands Academy of Arts and Sciences (KNAW) (project 10CDP037) and
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgments
We are indebted to the Netherlands Brain Bank (Director Dr. I. Huitinga) at the Netherlands Institute for Neuroscience for providing us with the brain material and patient information. We thank Dr. Michel A Hofman and Dr. Ronald WH Verwer for statistical assistance, Dr. Koen Bossers, Dr. Tian Zhou, Shangfeng Gao, Daniel J van Wamelen, Bart Fisser, Rawien A Balesar and Arja A Sluiter for their technical advice, and Wilma Verweij for her secretarial help.
References (43)
- et al.
CSF GABA in euthymic manic-depressive patients and controls
Biological Psychiatry
(1986) - et al.
Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density
Biological Psychiatry
(2003) - et al.
Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims
Brain Research
(1988) - et al.
The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia
Biological Psychiatry
(2002) - et al.
Postsynaptic density-membrane associated guanylate kinase proteins (PSD-MAGUKs) and their role in CNS disorders
Neuroscience
(2009) The role of glutamate on the action of antidepressants
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(2011)- et al.
Immunohistochemical and immunoblot study of GABA(A) alpha1 and beta2/3 subunits in the prefrontal cortex of subjects with schizophrenia and bipolar disorder
Neuroscience Research
(2004) - et al.
Brain GABA levels in patients with bipolar disorder
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(2009) - et al.
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression
Biological Psychiatry
(1999) - et al.
Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder
Biological Psychiatry
(2001)
Lithium effects on brain glutamatergic and GABAergic systems of healthy volunteers as measured by proton magnetic resonance spectroscopy
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Interaction of prefrontal cortical and hypothalamic systems in the pathogenesis of depression
Progress in Brain Research
Enlightening the postsynaptic density
Neuron
Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder
Neuropsychopharmacology
Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs
The Journal of Pharmacology and Experimental Therapeutics
Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease
Brain
Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression
Proceedings of the National Academy of Sciences of the United States of America
Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression
Brain Structure & Function
Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression
Neuropsychopharmacology
Corticotropin-releasing hormone, glutamate, and gamma-aminobutyric acid in depression
The Neuroscientist
Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy
Archives of General Psychiatry
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