Review
Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia

https://doi.org/10.1016/j.schres.2014.10.020Get rights and content

Abstract

Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20 years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5′ end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.

Section snippets

GABAergic dysfunction in schizophrenia — a brief chronology

Schizophrenia (SCZ) — a major psychiatric disorder with symptoms of delusions, hallucinations disorganized thought and affect, social withdrawal and apathy — lacks unifying neuropathology (Dorph-Petersen and Lewis, 2011, Catts et al., 2013), or narrowly defined genetic risk architectures and disease etiologies (Rodriguez-Murillo et al., 2012, Andreassen et al., 2014). Yet, clinical and translational research conducted over the last 40 years is beginning to identify major building blocks within

Altered expression of GABA synthesis enzyme GAD1 is one of the most frequently reported molecular alterations in the SCZ brain

The function of multiple subtypes of GABAergic neurons, including the aforementioned Chandelier cells, is thought to be compromised, at least in part, due to altered expression of GAD1 GABA synthesis enzyme (Lewis et al., 2005). GAD1 (GAD67) accounts for 80–90% of overall brain GABA, while 10–20% reflects the activity of a related gene, GAD2 (GAD65) (Asada et al., 1997, Condie et al., 1997). To date, there are at least 20 reports in the literature, conducted by multiple groups of investigators

Activity-dependent regulation of GABAergic gene expression in the rodent and primate brain

Given that various portions of the cerebral cortex show functional hypoactivity during various neuropsychological task performance in many cases with SCZ (Streit et al., 2001, Snitz et al., 2005), it is possible that some of the molecular and cellular changes observed in the SCZ brain could reflect secondary changes in response to alterations in neuronal activity. Indeed, a broad range of studies, from in vivo work with non-human primates to ex vivo studies in the cell culture dish, are in

Prefrontal GAD1 expression steadily increases during childhood and adolescence, and is sensitive to developmental pertubations

Maturation of the cerebral cortex, including its prefrontal areas, extends beyond the second decade of life (Kolb et al., 2012), and such type of prolonged developmental periods may play a key role in the neurobiology of SCZ as a psychiatric disorder with a typical onset of clinical symptoms around adolescence and young adulthood (Weinberger, 1987). Studies monitoring the expression and developmental trajectory of key molecules at inhibitory synapses in the primate prefrontal cortex during the

Developmental and disease-associated changes in epigenetic signatures at the GAD1 promoter

The regulatory networks governing the molecular architectures of cortical inhibitory circuitry are exceedingly complex and include a diverse array of transcriptional and post-transcriptional mechanisms. To mention just one recent example from the SCZ literature, prefrontal deficits in the expression of a subset of GABA neuron-specific mRNAs, including Neuropeptide (NPY), were found to be dependent on the regional supply of Brain-derived Neurotrophic Factor (BDNF), which in turn was subject to

Spatial architecture of the GAD1 locus in normal and diseased PFC

The preceding paragraph summarized evidence for localized epigenetic dysregulation of sequences surrounding the GAD1 transcription start site. However, the regulation of gene expression in a vertebrate cell goes far beyond the genetic and epigenetic architectures of proximal promoters and transcription start sites. Instead, chromosomes and gene expression units inside the cell nucleus are organized as highly complex dynamic 3-dimensional structures that include chromosomal loopings and

Synopsis and implications for future treatments of SCZ

If dysregulated GAD1 expression in PFC and other brain regions is indeed critical in the pathophysiology of at least some cases with SCZ, then one could speculate whether these mechanisms would offer novel therapeutic avenues for a subset of patients carrying this diagnosis. Of note, antipsychotic medications targeting dopaminergic, serotonergic and monoaminergic receptor systems are still the mainstay in SCZ treatment (Kim and Stahl, 2010, Taly, 2013) and broadly applied to a large majority of

Looking forward: targeted epigenetic interventions at the GAD1 locus for the treatment of SCZ

Genetic engineering-induced GAD1/GAD67 deficiency in cortical interneurons is detrimental for neuronal signaling and cognition and social interactions (Chattopadhyaya et al., 2007, Belforte et al., 2010, Lazarus et al., 2013, Schmidt et al., 2014). Whether or not an experimentally induced increase in Gad1/Gad67 would elicit therapeutic effects in preclinical SCZ models remains to be determined. Among the various options available in the present-day molecular toolbox for altering the expression

Role of funding source

Work in the authors' laboratory is supported by funds from the NIH (R01MH093332) and a Young Investigator Award to A.C.M. from the Brain & Behavior Research Foundation.

Contributors

Amanda Mitchell and Schahram Akbarian edited and drafted the manuscript. Yan Jiang and Cyril Peter drafted TALE and CRISPR images for the final figure. All authors reviewed the final manuscript.

Conflict of interest

The authors declare no conflicts of interest.

References (127)

  • K.A. Dorph-Petersen et al.

    Stereological approaches to identifying neuropathology in psychosis

    Biol. Psychiatry

    (2011)
  • S.M. Eack et al.

    Prefrontal cortical dysfunction during visual perspective-taking in schizophrenia

    Schizophr. Res.

    (2013)
  • S.L. Eastwood et al.

    Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia

    Schizophr. Res.

    (2005)
  • T. Gaj et al.

    ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering

    Trends Biotechnol.

    (2013)
  • J. Gilabert-Juan et al.

    Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients

    Neurosci. Lett.

    (2012)
  • S.H. Hendry et al.

    Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys

    Neuron

    (1988)
  • H.S. Huang et al.

    Chromatin immunoprecipitation in postmortem brain

    J. Neurosci. Methods

    (2006)
  • D. Joshi et al.

    Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia

    Biol. Psychiatry

    (2012)
  • S. Kapur et al.

    Half a century of antipsychotics and still a central role for dopamine D2 receptors

    Prog. Neuro-Psychopharmacol. Biol. Psychiatry

    (2003)
  • J.S. Lee et al.

    Involvement of the mirror neuron system in blunted affect in schizophrenia

    Schizophr. Res.

    (2014)
  • T.A. Lett et al.

    Treating working memory deficits in schizophrenia: a review of the neurobiology

    Biol. Psychiatry

    (2014)
  • M. Li et al.

    A cut above the rest: targeted genome editing technologies in human pluripotent stem cells

    J. Biol. Chem.

    (2014)
  • M. Mackowiak et al.

    Prenatal MAM administration affects histone H3 methylation in postnatal life in the rat medial prefrontal cortex

    Eur. Neuropsychopharmacol.

    (2014)
  • N. Mellios et al.

    Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia

    Biol. Psychiatry

    (2009)
  • K. Mirnics et al.

    Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex

    Neuron

    (2000)
  • A.C. Mitchell et al.

    The genome in three dimensions: a new frontier in human brain research

    Biol. Psychiatry

    (2014)
  • M. Ota et al.

    Pseudo-continuous arterial spin labeling MRI study of schizophrenic patients

    Schizophr. Res.

    (2014)
  • T.L. Perry et al.

    Gamma-aminobutyric-acid deficiency in brain of schizophrenic patients

    Lancet

    (1979)
  • C. Ribeiro de Almeida et al.

    The DNA-binding protein CTCF limits proximal Vkappa recombination and restricts kappa enhancer interactions to the immunoglobulin kappa light chain locus

    Immunity

    (2011)
  • E. Roberts et al.

    gamma-Aminobutyric acid in brain: its formation from glutamic acid

    J. Biol. Chem.

    (1950)
  • E. Roberts et al.

    Glutamic acid decarboxylase in brain

    J. Biol. Chem.

    (1951)
  • A.K. Shetty et al.

    Glutamic acid decarboxylase-67-positive hippocampal interneurons undergo a permanent reduction in number following kainic acid-induced degeneration of ca3 pyramidal neurons

    Exp. Neurol.

    (2001)
  • J.R. Smythies et al.

    Meeting report: biochemical aspects of schizophrenia. Alabama, April 1975

    Psychoneuroendocrinology

    (1975)
  • E.G. Spokes et al.

    Distribution of GABA in post-mortem brain tissue from control, psychotic and Huntington's chorea subjects

    J. Neurol. Sci.

    (1980)
  • A.M. Addington et al.

    GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

    Mol. Psychiatry

    (2005)
  • S. Akbarian et al.

    Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development

    Arch. Gen. Psychiatry

    (1993)
  • S. Akbarian et al.

    Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development

    Arch. Gen. Psychiatry

    (1993)
  • S. Akbarian et al.

    Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics

    Arch. Gen. Psychiatry

    (1995)
  • O.A. Andreassen et al.

    Boosting the power of schizophrenia genetics by leveraging new statistical tools

    Schizophr. Bull.

    (2014)
  • H. Asada et al.

    Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • J.E. Belforte et al.

    Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes

    Nat. Neurosci.

    (2010)
  • F.M. Benes et al.

    Increased density of glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain

    Cereb. Cortex

    (1992)
  • F.M. Benes et al.

    Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics

    J. Neurosci.

    (1992)
  • F.M. Benes et al.

    Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • D.L. Benson et al.

    Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys

    Cereb. Cortex

    (1994)
  • B.E. Bernstein et al.

    An integrated encyclopedia of DNA elements in the human genome

    Nature

    (2012)
  • R. Bharadwaj et al.

    Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia

    J. Neurosci.

    (2013)
  • E.D. Bird et al.

    Increased brain dopamine and reduced glutamic acid decarboxylase and choline acetyl transferase activity in schizophrenia and related psychoses

    Lancet

    (1977)
  • W.M. Bullock et al.

    Altered expression of genes involved in GABAergic transmission and neuromodulation of granule cell activity in the cerebellum of schizophrenia patients

    Am. J. Psychiatry

    (2008)
  • V.S. Catts et al.

    Rethinking schizophrenia in the context of normal neurodevelopment

    Front. Cell. Neurosci.

    (2013)
  • Cited by (45)

    • The prefrontal cortex as a target for atypical antipsychotics in schizophrenia, lessons of neurodevelopmental animal models

      2021, Progress in Neurobiology
      Citation Excerpt :

      GABAergic interneurons modulate pyramidal neuron activity. GABAergic transmission dysfunction in schizophrenia could be because of the lack of GABA synthesis evidenced by the decreased 67 kilodalton isoform of glutamic acid decarboxylase (GAD67, or GAD1) mRNA and protein level (Mitchell et al., 2015), which is notably in the PV positive cell population (Rocco et al., 2016). PV interneurons are classified by their localized synaptic contacts in pyramidal neurons: chandelier (innervate the axon initial segment) and basket cells (innervate soma and proximal dendrites), and their specific alterations in the PFC in schizophrenia are reviewed by Lewis et al. (2012).

    • γ-Aminobutyric acid

      2021, Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research
    View all citing articles on Scopus
    View full text