Brief report
Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients

https://doi.org/10.1016/j.jad.2012.01.013Get rights and content

Abstract

Background

The prefrontal cortex (PFC) is presumed to be involved in the pathogenesis of depression.

Methods

We determined the gene expression of 32 markers of the pathways of the two main neurotransmitters of the PFC, gamma-aminobutyric acid (GABA) and l-glutamic acid (glutamate), by real-time quantitative PCR in human postmortem anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) in elderly non-suicidal patients with major depressive disorder (MDD) or bipolar disorder (BD).

Results

We found the transcript levels of GABAA receptor beta 2 (GABRB2) and post-synaptic density-95 (PSD-95) to be significantly decreased in the ACC in mood disorder. DLPFC mRNA expression of all the detected genes in the mood disorder group did not differ significantly from that of the non-psychiatric controls.

Limitations

Several inherent and potentially confounding factors of a postmortem study, such as medication and cause of death, did not seem to affect the conclusions. The group size was relatively small but well documented, both clinically and neuropathologically.

Conclusions

The observed alterations in the GABAergic and glutamatergic pathways indicate a diminished activity. These alterations were only present in the ACC and not in the DLPFC.

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.

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