Differences between unipolar and bipolar I depression in the quantitative analysis of glutamic acid decarboxylase-immunoreactive neuropil

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.

Neuropathological and neuromorphometric abnormalities in bipolar disorder: View from the medial prefrontal cortical network

“…Postmortem interval, time of fixation, shrinkage, sex, age, and brain weight did not differ among the groups. Negative correlations between neuroleptic and/or lithium dose were reported in the medial temporal cortex and the OFC but not the DLPFC (Gos et al, 2012). These data were supported by a meta-analysis of Stanley Foundation Neuropathology Consortium samples (schizophrenia, BD, MDD, and controls, 15 per group) matched for age, gender, race, postmortem interval, mRNA quality, brain pH and hemisphere (Kim and Webster, 2010).…”

“…A recent immunohistochemistry study using a monoclonal antibody to both GAD 65 and GAD 67 reported a decrease in GADimmunoreactive neuropil in layers III and V of the left DLPFC in BD (n = 12) but not MDD (n = 9) subjects relative to controls (n = 18) (Gos et al, 2012). Duration of illness was greater in the BD group compared with the MDD group but did not correlate with GAD immunoreactivity in the DLPFC.…”

Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants

“…In the PFC, the overall results have been equivocal, with one study finding increased density of GAD-immunoreactive (IR) cells, 35 another finding significant decreases, 36 and a third finding no change. 37 Additionally, an investigation of GAD enzymatic activity in the PFC of suicide patients compared to healthy controls found no changes in GAD function. 38 Similarly, results in the orbitofrontal cortex, temporal cortex, and thalamus up to this point have had mixed results.…”

Differential diagnosis of major depression and bipolar disorder

“…In a metaanalysis, Kishi et al [5] are reporting two SNPs of the receptor gene to be associated with major depression and overlapping with bipolar disorder. Therefore, the neurobiological classification of subtypes of mood disorders is an unresolved challenge and alterations in GABA synthesis have been proposed to discriminate unipolar from bipolar I depression [6]. Discrimination of unipolar and bipolar depression at early stages of the illness could help improving specific treatment regimes.…”