Alterations of GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme of GABA synthesis.
Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLC), the entorhinal cortex (EC), the hippocampal formation, and the medial dorsal and lateral dorsal thalamic nuclei, with consecutive determination of GAD-immunoreactive (-ir) neuropil relative density. The study was performed on paraffin-embedded brains from 21 depressed patients (14 of whom had committed suicide) and 18 matched controls. The data were tested using Kruskal-Wallis, Mann-Whitney (U) and Spearman statistical procedures.
As shown by post-hoc U-tests, an increase in the relative density of GAD-ir neuropil was present in the hippocampal formation, specific for suicidal patients. The EC was the only area where non-suicidal patients also revealed an increase compared with controls. On the contrary, the DLC was the only area where a significant decrease existed, specific for non-suicidal patients. Numerous negative correlations were found between the investigated parameter and psychotropic medication.
A major limitation of this study is the relatively small case number. A further limitation is given by the lack of data on drug exposure across the whole life span. The possible impact of unipolar-bipolar dichotomy of mood disorders on the obtained results should also be considered.
The study, revealing predominantly an increased relative density of GAD-ir neuropil, suggests the diathesis of GABAergic system specific for depressed suicidal patients.
"A quantitative morphological analysis was performed in each of the selected sections as reported previously . The relative density of GAD-ir neuropil (the quotient of the area of fibres and/or synaptic endings and total measuring field area, see below) of depressed patients and controls was measured in neocortical areas: prefrontal [DLPFC, orbitofrontal (OFC) and pregenual anterior cingulate] and temporal [parahippocampal gyrus containing the entorhinal cortex (EC)], in the hippocampal formation [dentate gyrus (DG) and the CA1 field of the hippocampus (CA1)] and in thalamic nuclei (medial dorsal [MD] and LD). "
[Show abstract][Hide abstract] ABSTRACT: Alterations in GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme in GABA synthesis. This study aimed to differentiate between unipolar and bipolar I depression using quantitative evaluation of GAD-immunoreactive (GAD-ir) neuropil in several brain regions known to be involved in the pathophysiology of mood disorders. Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLPFC), the entorhinal cortex, the hippocampal formation and the medial dorsal and lateral dorsal (LD) thalamic nuclei, with a quantitative densitometric analysis of GAD-ir neuropil. The study was performed on paraffin-embedded brains from 9 unipolar and 12 bipolar I depressed patients (8 and 6 suicidal patients, respectively) and 18 matched controls. In unipolar patients, compared with controls, only the increased relative density of GAD-ir neuropil in the right LD was different from the previous results in depressed suicides from the same cohort (Gos et al. in J Affect Disord 113:45-55, 2009). On the other hand, the left DLPFC was the only area where a significant decrease was observed, specific for bipolar I depression. Significant differences between both diagnostic groups were found in these regions. By revealing abnormalities in the relative density of GAD-ir neuropil in brain structures, our study suggests a diathesis of the GABAergic system in mood disorders, which may differentiate the pathophysiology of unipolar from that of bipolar I depression.
European Archives of Psychiatry and Clinical Neuroscience 04/2012; 262(8). DOI:10.1007/s00406-012-0315-x · 3.53 Impact Factor
"Therefore, it is likely that reduced GAD-67 immunoreactivity in the dorsolateral PFC is due to a reduction in the density and size of calbindin-positive somata of GABAergic interneurons. Other postmortem studies investigating GAD in depression found reductions in GAD-65/67 immunopositive structures in the dorsolateral PFC (Gos et al., 2008) and in GAD protein level in the cerebellum (Fatemi et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the DLPFC (BA 9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (-34%) in depressed subjects compared to matched controls. Since recent neuroimaging studies have demonstrated that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in eight depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.
The International Journal of Neuropsychopharmacology 09/2009; 13(4):411-20. DOI:10.1017/S1461145709990587 · 4.01 Impact Factor
"in the GABAergic system might be associated with various pathological conditions including epilepsy, Parkinson's disease, Alzheimer's disease and mental illness (Kalueff and Nutt, 2007). In particular, increasing evidence suggests the possible involvement of GABA in the neuro - biology of mood disorder and the mechanisms of antidepressant action ( Gos et al . , 2009 ; Jinno and Kosaka , 2009 ; Sanacora and Saricicek , 2007 ) . It has been well established that the formation and recall of sensory , motor and cognitive representations require coordinated communication among multiple areas of the cerebral cortex , which"
[Show abstract][Hide abstract] ABSTRACT: GABA is a key mediator of neural activity in the mammalian central nervous system, and a diverse set of GABAergic neurons utilize GABA as a transmitter. It has been widely accepted that GABAergic neurons typically serve as interneurons while glutamatergic principal cells send excitatory signals to remote areas. In general, glutamatergic projection neurons monosynaptically innervate both principal cells and local GABAergic interneurons in each target area, and these GABAergic cells play a vital role in modulation of the activity of principal cells. The formation and recall of sensory, motor and cognitive representations require coordinated fast communication among multiple areas of the cerebral cortex, which are thought to be mostly mediated by glutamatergic neurons. However, there is an increasing body of evidence showing that specific subpopulations of cortical GABAergic neurons send long-range axonal projections to subcortical and other cortical areas. In particular, a variety of GABAergic neurons in the hippocampus project to neighboring and remote areas. Using anatomical, molecular and electrophysiological approaches, several types of GABAergic projection neurons have been shown to exist in the hippocampus. The target areas of these cells are the subiculum and other retrohippocampal areas, the medial septum and the contralateral dentate gyrus. The long-range GABAergic projection system of the hippocampus may serve to coordinate precisely the multiple activity patterns of widespread cortical cell assemblies in different brain states and among multiple functionally related areas.
Frontiers in Neuroanatomy 02/2009; 3:13. DOI:10.3389/neuro.05.013.2009 · 3.54 Impact Factor
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