Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.
ABSTRACT GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.
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ABSTRACT: Postmortem neuropathological studies of autism consistently reveal distinctive types of malformations, including cortical dysplasias, heterotopias, and various neuronomorphometric abnormalities. In keeping with these observations, we review here that 88% of high-risk genes for autism influence neural induction and early maturation of the neuroblast. In addition, 80% of these same genes influence later stages of differentiation, including neurite and synapse development, suggesting that these gene products exhibit long-lasting developmental effects on cell development as well as elements of redundancy in processes of neural proliferation, growth, and maturation. We also address the putative genetic overlap of autism with conditions like epilepsy and schizophrenia, with implications to shared and divergent etiologies. This review imports the necessity of a frameshift in our understanding of the neurodevelopmental basis of autism to include all stages of neuronal maturation, ranging from neural induction to synaptogenesis.Frontiers in Cellular Neuroscience 11/2014; 8:397. DOI:10.3389/fncel.2014.00397 · 4.18 Impact Factor
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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 his-tone 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 kilo-bases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including devel-opmentally 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. © 2014 Elsevier B.V. All rights reserved. 1. GABAergic dysfunction in schizophrenia — a brief chronology Schizophrenia (SCZ) — a major psychiatric disorder with symptoms of delusions, hallucinations disorganized thought and affect, social with-drawal 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 con-ducted over the last 40 years is beginning to identify major building blocks within the complex pathophysiology of SCZ. As highlighted in the various articles in this Special Issue of Schizophrenia Research, one such building block is the inhibitory GABAergic circuitry in the cerebral cortex. While the primary focus of our review will be on the transcrip-tional dysregulation of the glutamic acid decarboxylase 1 (GAD1) gene, encoding the 67 KDa GABA synthesis enzyme, we will begin with a brief synopsis of past studies in pursuit of the 'GABAergic hypothesis of SCZ', which proposes that GABAergic systems could play a key role in the pathophysiology of SCZ. This idea is not new. Thus, 25 years after the first reports described the relatively large amounts of GABA and high levels of glutamic acid decarboxylase (GAD) in the brain (Roberts and Frankel, 1950, 1951), the role of inhibitory inputs to midbrain dopaminergic neurons was hypothesized to be the key mechanism responsible for excessive and dysregulated dopaminergic activity in psychosis (Stevens et al., 1974; Smythies et al., 1975). While it was quickly recognized that a generalized deficit in GABA sig-naling is not a characteristic of SCZ — as the symptoms of psychosis remained unresponsive to GABA agonists in early clinical trials (Tamminga et al., 1978) — the idea of region-specific dysfunctions of GABA systems nonetheless continued, up to the present day, to main-tain significant traction and in fact, emerged as one of the most popular hypotheses in SCZ research. For example, several studies reported a decrease in GABA levels and GAD activity in the medial temporal lobe, thalamus and ventral striatum of the SCZ postmortem brain (Bird et al., 1977; Perry et al., 1979; Spokes et al., 1980) albeit other investiga-tors reported negative findings (Cross et al., 1979). There were also re-ports on low GABA levels in the cerebrospinal fluid in at least a subset of patients diagnosed with SCZ (Lichtshtein et al., 1978; van Kammen et al., 1982). Following these early studies on GABA and GAD quantifica-tions in the schizophrenic brain, several papers explored alterations in the inhibitory system in the context of abnormal circuitry. This type of work was mainly focused on the cerebral cortex and hippocampus, starting with Benes' model proposing excessive excitatory and insuffi-cient inhibitory signaling in the upper layers of the cerebral cortex due to a possible loss of GABAergic neurons and/or supranormal numbers or densities of glutamatergic afferent input into the same cortical layers (Benes et al., 1992a,b). There is also an ongoing discussion if and how decreased expression of GABAergic marker genes in the cerebral cortex Schizophrenia Research xxx (2014) xxx–xxx ⁎ Corresponding author.Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.020 · 4.43 Impact Factor
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ABSTRACT: Adolescence is a period of developmental flux when brain systems are vulnerable to influences of early substance use, which in turn relays increased risk for substance use disorders. Our study intent was to assess adolescent regional cerebral blood flow (rCBF) as it relates to current and future alcohol use. The aim was to identify brain-based predictors for initiation of alcohol use and onset of future substance use disorders.