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occipital cortex were also found during treatment of medicated with antidepressants at the time of death,
MDD with serotonergic antidepressants. [13] suggesting that GAD and GAD might play a role in
65 67
depressive syndromes. [41] Fatemi et al. [42] investigated
Significantly lower levels of GABA were observed in the cerebellar levels of Reelin 410, 330 and 180 kDa,
the anterior cingulate cortex (ACC) of adolescents with GAD , and GAD in subjects with BD, schizophrenia,
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65
MDD compared with healthy subjects. [27] Levels were MDD, and controls using the well‑characterized
measured by the means of proton magnetic resonance Stanley Brain Consortium Collection. They found
spectroscopy and expressed as ratios to unsuppressed a reduction in levels of GAD and GAD proteins
65
67
voxel tissue water (VTW). In this age group, significant in all psychiatric subjects. These findings could
differences were found for the ratio GABA/VTW in explain increased blood and CSF GLU and glutamine
the ACC of adolescents with and without anhedonia levels in schizophrenic, [43,44] and depressed subjects, [45]
but not in those nonanhedonic compared to healthy probably due to an accumulation of these two precursor
controls. [27] compounds of GABA. Indeed, normal production of
GAD and GAD , as well as of Reelin 410, 330 and
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65
GABA PATHWAY‑FOCUS ON GAD 180 kDa, reflects normal GABAergic cell function in
several parts of the brain including cerebellum. [46]
GABA is synthesized from GLU via decarboxylation Of note, Reelin, a protein responsible for correct
by GAD, a pyridoxal phosphate‑dependent enzyme. [28] lamination of the CNS during the embryonic period,
Studies of GAD began in the early 50s with the work may be involved in the etiology of schizophrenia, BD,
of Roberts and Frankel, [29,30] and Awapara [31] who and autism. [47‑54] Remarkably, deficits in CNS levels
independently discovered that GABA is synthesized
in GABAergic neurons in CNS. However, GAD and of Reelin can affect memory processing, learning,
GABA were also detected in the pancreas where synaptic organization, and cognition in the adult
[55]
the latter is stored in synaptic‑like vesicles in islet brain.
beta cells. [32‑34] GAD exists in two isoforms: one of Interestingly, GAD appeared to be a promising
a molecular size of 65 kDa is termed GAD , whilst 67
65 biomarker for BD and schizophrenia since it
the other, of 67 kDa, is termed GAD . Each of them
67 discriminated these illnesses among a number of
plays a distinct role: GAD is the product of a gene
65 psychiatric conditions with relatively high specificity
located on chromosome 10 whereas GAD gene is
67 and sensitivity. [56] Moreover, decreased levels of GAD
on chromosome 2. [35‑37] These two proteins appear
to be essential for maintaining homeostasis and were found in the postmortem left DLPFC of BD
viability of complex organisms. Studies carried out patients compared with MDD individuals and controls,
in GAD knockout mice showed a reduction in the giving rise to the possibility of differentiating the brain
67 areas involved in unipolar and bipolar depression.
levels of GABA and died at the birth of a severe cleft
palate. [38] Instead GAD knockout mice presented Heckers and colleagues first made the description of
65 the distribution of GAD and GAD mRNA‑positive
normal basal levels of GABA and appear normal at 65 67
birth but developed fatal seizures and anxiety‑like neurons in the human hippocampus. [57] They found
phenotypes. [39] The two isoforms were localized that abnormalities of hippocampal GAD expression
in different neuronal compartments. GAD lies are more prominent in BD than in schizophrenia,
65
primarily in axon terminals and synthesizes GABA for whereas another study showed a larger reduction
neuronal transmission. GAD is widely distributed of GAD mRNA‑containing neurons in BD patients
67
67 [58]
throughout the neuron for the synthesis of GABA for than in those with schizophrenia. Of interest is
general metabolic activity. [35,36,40] the evidence that decreased GAD expression leads
67
to a reduction of levels of GABA, with a net effect
GAD IN MDs of a reduced GABAergic inhibitory control over
glutamatergic cells. Therefore, it has been hypothesized
A substantial amount of evidence has suggested a that GAD levels could be a surrogate marker for
67
role of GAD in MDs. Karolewicz et al. [41] measured psychosis liability [59] and pharmacological agents that
the levels of GAD and GAD in postmortem brain raise GAD expression levels could represent novel
67
65
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samples from the gray matter of left dorsolateral targets for antipsychotic therapy. [59] Taken together,
prefrontal cortex (DLPFC, Brodmann’s Area 9) of MDD these findings demonstrate that GAD might have a role
patients, treated and untreated with antidepressants. in modulating the psychopathological presentation in
GAD and GAD were reduced in antidepressant‑free a distinct subset of patients with MDs, possibly those
65
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MDD subjects compared to matched controls. with more prominent mood‑congruent or incongruent
This reduction was not present in MDD patients psychotic features.

238 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 239