Skip to main content
    • Aa
    • Aa

GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders

  • Etienne Sibille (a1) (a2), Harvey M. Morris (a3) (a2), Rama S. Kota (a1) and David A. Lewis (a1) (a3) (a2)

Reduced cortical γ-aminobutyric acid (GABA) levels and altered markers for subpopulations of GABA interneurons have been reported in major depressive disorder (MDD) by in-vivo brain imaging and post-mortem histological studies. Subgroups of GABA interneurons exert differential inhibitory control on principal pyramidal neurons and can be identified based on the non-overlapping expression of the calcium-binding proteins parvalbumin (PV) or calretinin (CR) or the neuropeptide somatostatin (SST). As altered markers of GABAergic functions may also be present in bipolar disorder (BPD), the specificity of particular GABA-related molecular deficits in mood disorders is not known. We used real-time quantitative polymerase chain reaction (qPCR) to assess expression levels of two GABA synthesizing enzymes (glutamate decarboxylase; GAD65 and GAD67) and of three markers of GABA neuron subpopulations (PV, CR, SST) in the dorsolateral prefrontal cortex (DLPFC; Brodmann area 9) in triads (n=19) of control subjects and matched subjects with BPD or MDD. BPD subjects demonstrated significantly reduced PV mRNA, trend level reduction in SST mRNA and no alterations in GAD67, GAD65, or CR mRNA levels; MDD subjects demonstrated reduced SST mRNA expression without alterations in the other transcripts. The characteristic age-related decline in SST expression was not observed in MDD, as low expression was detected across age in MDD subjects. After controlling for age, MDD subjects demonstrated significantly reduced SST mRNA expression. Decreased SST levels in MDD were confirmed at the protein precursor level. Results were not explained by other clinical, demographic or technical parameters. In summary, MDD was characterized by low DLPFC SST, whereas decreased PV mRNA appears to distinguish BPD from MDD.

Corresponding author
Address for correspondence: E. Sibille, Ph.D., University of Pittsburgh, Department of Psychiatry, 3811 O'Hara Street, BST W1643, Pittsburgh, PA 15213, USA. Tel.: 412-624-0804Fax: 412-624-9910Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

S Akbarian , HS Huang (2006). Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Research Reviews 52, 293304.

MS Ansorge , M Zhou , A Lira , R Hen , (2004). Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306, 879881.

CL Beasley , ZJ Zhang , I Patten , GP Reynolds (2002). Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biological Psychiatry 52, 708715.

M Cahir , I Costello , DJ King , GP Reynolds (2005). Chronic haloperidol or clozapine treatment does not alter parvalbumin immunoreactivity in the rat frontal cortex or hippocampus. Neuroscience Letters 373, 5760.

D Cotter , S Landau , C Beasley , R Stevenson , (2002). 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 51, 377386.

D Cotter , D Mackay , S Landau , R Kerwin , (2001). Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Archives of General Psychiatry 58, 545553.

J DeFelipe (1997). Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex. Journal of Chemical Neuroanatomy 14, 119.

E Engin , J Stellbrink , D Treit , CT Dickson (2008). Anxiolytic and antidepressant effects of intracerebroventricularly administered somatostatin: behavioral and neurophysiological evidence. Neuroscience 157, 666676.

L Erraji-BenChekroun , MD Underwood , V Arango , HC Galfalvy , (2005). Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biological Psychiatry 57, 549558.

PL Gabbott , SJ Bacon (1996). Local circuit neurons in the medial prefrontal cortex (areas 24a,b,c, 25 and 32) in the monkey: I. Cell morphology and morphometrics. Journal of Comparative Neurology 364, 567608.

LA Glantz , MC Austin , DA Lewis (2000). Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia. Biological Psychiatry 48, 389397.

C Glorioso , M Sabatini , T Unger , T Hashimoto , (2006). Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood. Molecular Psychiatry 11, 633648.

MC Gonzalez-Albo , GN Elston , J DeFelipe (2001). The human temporal cortex: characterization of neurons expressing nitric oxide synthase, neuropeptides and calcium-binding proteins, and their glutamate receptor subunit profiles. Cerebral Cortex 11, 11701181.

A Guidotti , J Auta , JM Davis , V Giorgi-Gerevini , (2000). Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Archivees of General Psychiatry 57, 10611069.

T Hashimoto , HH Bazmi , K Mirnics , Q Wu , (2008). Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. American Journal of Psychiatry 165, 479489.

T Hashimoto , SE Bergen , QL Nguyen , B Xu , (2005). Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. Journal of Neuroscience 25, 372383.

M Hayashi , A Yamashita , K Shimizu (1997). Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNAs during aging. Brain Research 749, 283289.

TL Hayes , JL Cameron , JD Fernstrom , DA Lewis (1991). A comparative analysis of the distribution of prosomatostatin-derived peptides in human and monkey neocortex. Journal of Comparative Neurology 303, 584599.

S Imbeaud , E Graudens , V Boulanger , X Barlet , (2005). Towards standardization of RNA quality assessment using user-independent classifiers of microcapillary electrophoresis traces. Nucleic Acids Research 33, 112.

TA Klempan , A Sequeira , L Canetti , A Lalovic , (2009). Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Molecular Psychiatry 14, 175189.

MA Kling , DR Rubinow , AR Doran , A Roy , (1993). Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion. Neuroendocrinology 57, 7988.

C Konradi , M Eaton , ML MacDonald , J Walsh , (2004). Molecular evidence for mitochondrial dysfunction in bipolar disorder. Archivers of General Psychiatry 61, 300308.

AJ Levinson , PB Fitzgerald , G Favalli , DM Blumberger , (2010). Evidence of cortical inhibitory deficits in major depressive disorder. Biological Psychiatry 67, 458464.

DA Lewis , G Gonzalez-Burgos (2008). Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 33, 141165.

DA Lewis , B Moghaddam (2006). Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Archives of Neurology 63, 13721376.

JE Lisman , JT Coyle , RW Green , DC Javitt , (2008). Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends in Neuroscience 31, 234242.

D Maciag , J Hughes , G O'Dwyer , Y Pride , (2010). Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biological Psychiatry 67, 465470.

N Mellios , HS Huang , SP Baker , M Galdzicka , (2009). Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biological Psychiatry 65, 10061014.

HM Morris , T Hashimoto , DA Lewis (2008). Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder. Cerebral Cortex 18, 15751587.

EJ Nestler , M Barrot , RJ DiLeone , AJ Eisch , (2002). Neurobiology of depression. Neuron 34, 1325.

D Ongur , WC Drevets , JL Price (1998). Glial reduction in the subgenual prefrontal cortex in mood disorders. Proceedings of the National Academy of Sciences USA 95, 1329013295.

E Pallis , A Vasilaki , D Fehlmann , A Kastellakis , (2009). Antidepressants influence somatostatin levels and receptor pharmacology in brain. Neuropsychopharmacology 34, 952963.

H Pantazopoulos , N Lange , RJ Baldessarini , S Berretta (2007). Parvalbumin neurons in the entorhinal cortex of subjects diagnosed with bipolar disorder or schizophrenia. Biological Psychiatry 61, 640652.

JB Potash (2006). Carving chaos: genetics and the classification of mood and psychotic syndromes. Harvard Review of Psychiatry 14, 4763.

G Rajkowska , JJ Miguel-Hidalgo , J Wei , G Dilley , (1999). Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biological Psychiatry 45, 10851098.

G Rajkowska , G O'Dwyer , Z Teleki , CA Stockmeier , (2007). GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 32, 471482.

DR Rubinow , CL Davis , RM Post (1988). Somatostatin in neuropsychiatric disorders. Progress in Neuropsychopharmacological and Biological Psychiatry 12(Suppl.), S137S155.

DR Rubinow , PW Gold , RM Post , JC Ballenger , (1983). CSF somatostatin in affective illness. Archives of General Psychiatry 40, 409412.

G Sanacora , R Gueorguieva , CN Epperson , YT Wu , (2004). Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Archives of General Psychiatry 61, 705713.

G Sanacora , GF Mason , DL Rothman , KL Behar , (1999). Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Archives of General Psychiatry 56, 10431047.

G Sanacora , GF Mason , DL Rothman , F Hyder , (2003). Increased cortical GABA concentrations in depressed patients receiving ECT. American Journal of Psychiatry 160, 577579.

G Sanacora , GF Mason , DL Rothman , JH Krystal (2002). Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. American Journal of Psychiatry 159, 663665.

SG Schwab , DB Wildenauer (2000). Chromosome 22 workshop report. American Journal of Medical Genetics 88, 276278.

A Sequeira , T Klempan , L Canetti , J Ffrench-Mullen , (2007). Patterns of gene expression in the limbic system of suicides with and without major depression. Molecular Psychiatry 12, 640655.

A Sequeira , F Mamdani , C Ernst , MP Vawter , (2009). Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4, e6585.

E Sibille , DA Lewis (2006). SERT-ainly involved in depression, but when? American Journal of Psychiatry 163, 8–11.

A Surget , Y Wang , S Leman , Y Ibarguen-Vargas , (2009). Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal. Neuropsychopharmacology 34, 13631380.

GW Valentine , G Sanacora (2009). Targeting glial physiology and glutamate cycling in the treatment of depression. Biochemical Pharmacology 78, 431439.

J Vandesompele , K De Preter , F Pattyn , B Poppe , (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biology 3, 34.134.11.

J Vela , A Gutierrez , J Vitorica , D Ruano (2003). Rat hippocampal GABAergic molecular markers are differentially affected by ageing. Journal of Neurochemistry 85, 368377.

DW Volk , MC Austin , JN Pierri , AR Sampson , (2000). Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Archives of General Psychiatry 57, 237245.

G Weckbecker , I Lewis , R Albert , HA Schmid , (2003). Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nature Reviews Drug Discovery 2, 999–1017.

CS Weickert , TM Hyde , BK Lipska , MM Herman , (2003). Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 8, 592610.

MC Whitlock (2005). Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. Journal of Evolutionary Biology 18, 13681373.

TU Woo , AM Kim , E Viscidi (2008). Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia. Brain Research 1218, 267277.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Sibille Supplementary Materials
Sibille Supplementary Tables

 Word (44 KB)
44 KB