ReviewTranscriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with 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.
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2021, Progress in NeurobiologyCitation 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).
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