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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- "Alterations observed include a shift from facilitative towards repressive chromatin-associated histone modifications, and changes in DNA methylation signatures, often in conjunction with altered GAD1 expression in the prefrontal cortex (PFC) of the affected SCZ cases (Huang and Akbarian, 2007; Huang et al., 2007; Tang et al., 2011; Grayson and Guidotti, 2013). It is also noteworthy that common polymorphisms in the proximal GAD1 promoter conferred genetic risk for SCZ, impaired working memory performance and accelerated loss of gray matter (Addington et al., 2005; Straub et al., 2007), possibly in conjunction with altered expression of the cation chloride co-transporters NKCC1/KCC2, two key regulators of postsynaptic GABA A receptor-mediated currents (Hyde et al., 2011). These findings, taken together, would suggest that the genetic and epigenetic architecture of the GAD1 promoter is a potential factor for the gene's dysregulated expression in at least some cases with SCZ. "
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.Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.020 · 4.43 Impact Factor
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- "Using quantitative PCR and laser microdissection to collect RNA from individual Layer 3 PCs of monkey DLPFC, we found that the levels of KCC2 and NKCC1 mRNA were constant during postnatal development (Supplementary Fig. 6A). These data, together with previous studies (Hyde et al. 2011), suggest that in human and monkey DLPFC the hyperpolarizing shift in V in occurs before birth. However, mRNA levels do not give information on protein expression, and, indeed, KCC2 protein levels in human neocortex increase during postnatal development (Dzhala et al. 2005). "
ABSTRACT: Development of inhibition onto pyramidal cells may be crucial for the emergence of cortical network activity, including gamma oscillations. In primate dorsolateral prefrontal cortex (DLPFC), inhibitory synaptogenesis starts in utero and inhibitory synapse density reaches adult levels before birth. However, in DLPFC, the expression levels of γ-aminobutyric acid (GABA) synapse-related gene products changes markedly during development until young adult age, suggesting a highly protracted maturation of GABA synapse function. Therefore, we examined the development of GABA synapses by recording GABAAR-mediated inhibitory postsynaptic currents (GABAAR-IPSCs) from pyramidal cells in the DLPFC of neonatal, prepubertal, peripubertal, and adult macaque monkeys. We found that the decay of GABAAR-IPSCs, possibly including those from parvalbumin-positive GABA neurons, shortened by prepubertal age, while their amplitude increased until the peripubertal period. Interestingly, both GABAAR-mediated quantal response size, estimated by miniature GABAAR-IPSCs, and the density of GABAAR synaptic appositions, measured with immunofluorescence microscopy, were stable with age. Simulations in a computational model network with constant GABA synapse density showed that the developmental changes in GABAAR-IPSC properties had a significant impact on oscillatory activity and predicted that, whereas DLPFC circuits can generate gamma frequency oscillations by prepubertal age, mature levels of gamma band power are attained at late stages of development.Cerebral Cortex 06/2014; DOI:10.1093/cercor/bhu122 · 8.67 Impact Factor
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- "parahippocampal gyrus and prefrontal cortex [Eastwood and Harrison, 2005]. Current evidence points to several mechanisms that may cause subtle impairment in cortical development in schizophrenia, including both genetic and adverse environmental factors [Hyde et al., 2011; Kang et al., 2011; Lodge and Grace, 2011]. "
ABSTRACT: Schizophrenia is assumed to be a neurodevelopmental disorder, which might involve disturbed development of the cerebral cortex, especially in frontal and medial temporal areas. Based on a novel spherical harmonics approach to measuring complexity of cortical folding, we applied a measure based on fractal dimension (FD) to investigate the heterogeneity of regional cortical surface abnormalities across subgroups of schizophrenia defined by symptom profiles. A sample of 87 patients with DSM-IV schizophrenia was divided into three subgroups (based on symptom profiles) with predominantly negative (n = 31), disorganized (n = 23), and paranoid (n = 33) symptoms and each compared to 108 matched healthy controls. While global FD measures were reduced in the right hemisphere of the negative and paranoid subgroups, regional analysis revealed marked heterogeneity of regional FD alterations. The negative subgroup showed most prominent reductions in left anterior cingulate, superior frontal, frontopolar, as well as right superior frontal and superior parietal cortices. The disorganized subgroup showed reductions in bilateral ventrolateral/orbitofrontal cortices, and several increases in the left hemisphere, including inferior parietal, middle temporal, and midcingulate areas. The paranoid subgroup showed only few changes, including decreases in the right superior parietal and left fusiform region, and increase in the left posterior cingulate cortex. Our findings suggest regional heterogeneity of cortical folding complexity, which might be related to biological subgroups of schizophrenia with differing degrees of altered cortical developmental pathology. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.Human Brain Mapping 04/2014; 35(4). DOI:10.1002/hbm.22283 · 6.92 Impact Factor