Receptor Subunit Genes Research Articles

GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence

Gamma-aminobutyric acid (GABA) A receptors are believed to mediate some of the physiological and behavioral actions of ethanol. Recent studies have suggested that genetic variants of the GABA-A receptor alpha2 subunit gene (GABRA2) are associated with alcohol dependence. The aim of this study is to confirm and extend the role of GABRA2 haplotypes in the liability to alcohol dependence. 291 (231 male) treatment-seeking alcohol-dependent individuals and 295 (153 male) control subjects were enrolled into the study. Characteristics of alcohol dependence were obtained using the SSAGA (semi-structured assessment of the genetics of alcoholism, German Version). Genotyping of 10 SNPs across the GABRA2 gene was performed following previous reports and using PCR. One genetic variant was detected to significantly differ between alcohol-dependent subjects and controls. Two common 8 SNP haplotypes and their complementary alleles were identified containing this SNP and were present in 89.9% of controls and 93.4% of the alcohol-dependent individuals. One of the haplotypes (T-C-A-C-A-T-T-C) was significantly associated with alcohol dependence and characteristics of alcohol withdrawal and severity of alcohol dependence (delirium tremens, withdrawal seizures). These findings support and extend the three previous studies implicating a GABA-A receptor subunit as contributing to the genetic risk for alcohol dependence. Possible implications of these findings are discussed.

Positional clustering improves computational binding site detection and identifies novel cis -regulatory sites in mammalian GABA A receptor subunit genes

Understanding transcription factor (TF) mediated control of gene expression remains a major challenge at the interface of computational and experimental biology. Computational techniques predicting TF-binding site specificity are frequently unreliable. On the other hand, comprehensive experimental validation is difficult and time consuming. We introduce a simple strategy that dramatically improves robustness and accuracy of computational binding site prediction. First, we evaluate the rate of recurrence of computational TFBS predictions by commonly used sampling procedures. We find that the vast majority of results are biologically meaningless. However clustering results based on nucleotide position improves predictive power. Additionally, we find that positional clustering increases robustness to long or imperfectly selected input sequences. Positional clustering can also be used as a mechanism to integrate results from multiple sampling approaches for improvements in accuracy over each one alone. Finally, we predict and validate regulatory sequences partially responsible for transcriptional control of the mammalian type A γ-aminobutyric acid receptor (GABAAR) subunit genes. Positional clustering is useful for improving computational binding site predictions, with potential application to improving our understanding of mammalian gene expression. In particular, predicted regulatory mechanisms in the mammalian GABAAR subunit gene family may open new avenues of research towards understanding this pharmacologically important neurotransmitter receptor system.

Maternal Exposure of Low Dose of TCDD Modulates the Expression of Estrogen Receptor Subunits of Male Gonads in Offspring

We have analyzed the effects of low-dose transplacental and lactational exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression relating to the dioxin and sexual hormone cascade, and demonstrated the effects on testicular growth and sexual maturation in male offspring rats. TCDD (10 ng/kg) was administered to dams on Days 7 and 14 of gestation, and on Days 0, 7 and 14 after delivery. Gene expression of cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) in the liver of 17-day-old rats was significantly increased compared with controls. Furthermore, expression of estrogen receptors (ER)alpha and ERbeta was significantly increased at 17 and 42 days old, respectively in the testis of TCDD-administered rats compared with controls. Although testicular weight and the seminiferous tubule diameter were increased in 17-day-old rats, there was no difference in the number of germ cells between TCDD-treated and control animals. The expressions of androgen receptor and inhibin subunit genes were not significantly changed. These findings suggest that low-dose exposure of TCDD leads to unusual development of the testis by perturbation of steroid hormone homeostasis.

(What to Do) When Epilepsy Gene Mutations Stop Making Sense

(What to Do) When Epilepsy Gene Mutations Stop Making Sense

In silico comparative genomic analysis of GABAA receptor transcriptional regulation

BackgroundSubtypes of the GABAA receptor subunit exhibit diverse temporal and spatial expression patterns. In silico comparative analysis was used to predict transcriptional regulatory features in individual mammalian GABAA receptor subunit genes, and to identify potential transcriptional regulatory components involved in the coordinate regulation of the GABAA receptor gene clusters.ResultsPreviously unreported putative promoters were identified for the β2, γ1, γ3, ε, θ and π subunit genes. Putative core elements and proximal transcriptional factors were identified within these predicted promoters, and within the experimentally determined promoters of other subunit genes. Conserved intergenic regions of sequence in the mammalian GABAA receptor gene cluster comprising the α1, β2, γ2 and α6 subunits were identified as potential long range transcriptional regulatory components involved in the coordinate regulation of these genes. A region of predicted DNase I hypersensitive sites within the cluster may contain transcriptional regulatory features coordinating gene expression. A novel model is proposed for the coordinate control of the gene cluster and parallel expression of the α1 and β2 subunits, based upon the selective action of putative Scaffold/Matrix Attachment Regions (S/MARs).ConclusionThe putative regulatory features identified by genomic analysis of GABAA receptor genes were substantiated by cross-species comparative analysis and now require experimental verification. The proposed model for the coordinate regulation of genes in the cluster accounts for the head-to-head orientation and parallel expression of the α1 and β2 subunit genes, and for the disruption of transcription caused by insertion of a neomycin gene in the close vicinity of the α6 gene, which is proximal to a putative critical S/MAR.

Characterization of the nicotinic acetylcholine receptor subunit gene Mdα2 from the house fly, Musca domestica

AbstractA nicotinic acetylcholine receptor (nAChR) subunit gene, Mdα2, was isolated and characterized from the house fly, Musca domestica. This is the first nAChR family member cloned from house flies. Mdα2 had a cDNA of 2,607 bp, which included a 696 bp 5′‐untranslated region (UTR), an open reading frame of 1,692 bp, and a 219 bp 3′‐UTR. Its deduced amino acid sequence possesses the typical characteristics of nAChRs. Mdα2 genomic sequence was 11.2 kb in length in the aabys strain and 10.9 kb in the OCR strain, including eight exons and seven introns. Based on the deduced amino acid sequence, Mdα2 had the closest phylogenetic relationship to the Drosophila melanogaster Dα2 and Anopheles gambiae Agamα2, and a similar genomic structure to Dα2. Quantitative real‐time PCR analysis showed that Mdα2 is expressed in the head and the thorax at 150‐ and 8.5‐fold higher levels than in the abdomen. Linkage analysis of a Mdα2 polymorphism indicates this gene is on autosome 2. The importance of these results in understanding the diversity and phylogenetic relationships of insect nAChRs, the physiology of nAChRs in the house fly, and the utility of nAChR sequences in resistance detection/monitoring is discussed. Arch. Insect Biochem. Physiol. 64:30–42, 2007. © 2006 Wiley‐Liss, Inc.

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Selected mutations in the human alpha4 or beta2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

GABAA receptors form heteromeric GABA-gated chloride channels assembled from a large family of subunit genes. In cerebellum, distinct GABAA receptor subtypes, differing in subunit composition, are segregated between cell types and synaptic circuits. The cerebellum therefore represents a useful system to investigate the significance of GABAA receptor heterogeneity. For instance, studies of mice carrying targeted deletion of major GABAA receptor subunit genes revealed the role of alpha subunit variants for receptor assembly, synaptic targeting, and functional properties. In addition, these studies unraveled mandatory association between certain subunits and demonstrated distinct pharmacology of receptors mediating phasic and tonic inhibition. Although some of these mutants have a profound loss of GABAA receptors, they exhibit only minor impairment of motor function, suggesting activation of compensatory mechanisms to preserve inhibitory networks in the cerebellum. These adaptations include an altered balance between phasic and tonic inhibition, activation of voltage-independent K+ conductances, and upregulation of GABAA receptors in interneurons that are not affected directly by the mutation. Deletion of the alpha1 subunit gene leads to complete loss of GABAA receptors in Purkinje cells. A striking alteration occurs in these mice, whereby presynaptic GABAergic terminals are preserved in the molecular layer but make heterologous synapses with spines, characterized by a glutamatergic-like postsynaptic density. During development of alpha1(0/0) mice, GABAergic synapses are initially formed but are replaced upon spine maturation. These findings suggest that functional GABAA receptors are required for long-term maintenance of GABAergic synapses in Purkinje cells.

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Novel G423S Mutation of Human α7 Nicotinic Receptor Promotes Agonist-Induced Desensitization by a Protein Kinase C-Dependent Mechanism

The alpha7 nicotinic acetylcholine receptor subunit (CHRNA7) gene harbors a high degree of polymorphism. In this study, we found a novel variant (1267 G to A) in exon 10 of the CHRNA7 gene in a Japanese population. This variant results in glycine-to-serine substitution at position 423 (G423S) located in the large cytoplasmic loop of the protein. To clarify the possibility that the G423S mutation alters the pharmacological properties of alpha7 receptors, acetylcholine (ACh)-elicited current through alpha7-G423S mutant receptors expressed in Xenopus laevis oocytes was measured using the two-electrode voltage-clamp technique. We found that the current elicited by ACh (1 mM, 5 s) through alpha7-G423S receptors, but not through alpha7 receptors, was significantly decreased by treatment with a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA, 10-30 nM). In addition, PMA (10 nM) selectively promoted a progressive decrease in alpha7-G423S current induced by repetitive application of ACh pulses (1 mM, 0.1 s, 0.17-0.33 Hz) compared with alpha7 current. PMA also enhanced the inactivation of alpha7-G423S mutant receptors induced by a prolonged application of choline (30 microM) without affecting alpha7 receptor responses. Western blot analysis showed that the treatment with PMA (30 nM) increased the serine phosphorylation level of the alpha7-G423S mutant receptors but not that of the wild-type receptors. These findings demonstrate that the G423S mutation promotes receptor desensitization by a protein kinase C-dependent mechanism. Thus, we provide the first evidence that a variant in the human CHRNA7 gene alters the function of alpha7 nicotinic receptors.

Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia

Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit ( CHRNA7) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A, a partially duplicated gene 1.6 Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy–Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients ( p = 0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed.

Early postnatal chronic inflammation produces long‐term changes in pain behavior and N‐methyl‐D‐aspartate receptor subtype gene expression in the central nervous system of adult mice

The objective of this study was to test whether postnatal chronic inflammation resulted in altered reactivity to pain later in life when reexposed to the same inflammatory agent and whether this alteration correlated with brain-region-specific patterns of N-methyl-D-aspartate (NMDA) receptor subtype gene expression. Neonatal mouse pups received a single injection of complete Freund's adjuvant (CFA) or saline into the left hind paw on postnatal day 1 or 14. At 12 weeks of age, both neonatal CFA- and saline-treated animals received a unilateral injection of CFA in the left hind paw. Adult behavioral responsiveness of the left paw to a radiant heat source was determined in mice treated neonatally with saline or CFA before and after receiving CFA as adults. Twenty-four hours later, brains were dissected and NMDA receptor subunit gene expression was determined in four different brain areas by using an RNase protection assay. The results indicated that NMDA receptor subtype gene expression in adult mice exposed to persistent neonatal peripheral inflammation was brain region specific and that NMDA gene expression and pain reactivity differed according to the day of neonatal CFA exposure. Similarly, adult behavioral responsiveness to a noxious radiant heat source differed according to the age of neonatal exposure to CFA. The data suggest a possible molecular basis for the hypothesis that chronic persistent inflammation experienced early during development may permanently alter the future behavior and the sensitivity to pain later in life, especially in response to subsequent or recurrent inflammatory events.

Significant linkage and association between a functional (GT)n polymorphism in promoter of the N-methyl- d-aspartate receptor subunit gene ( GRIN2A) and schizophrenia

Dysfunction of the N-methyl- d-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Previous study identified a variable (GT)n polymorphism in the promoter region of the N-methyl- d-aspartate (NMDA) subunit gene ( GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. Our present study was aimed at confirming the association of the (GT)n polymorphism of GRIN2A promoter with schizophrenia using 122 Han Chinese sib-pair families. Non-parametric linkage analysis and transmission/disequilibrium test (TDT) were undertaken using the GENEHUNTER, v2.1. In non-parametric linkage analysis, suggestive linkage was found for the (GT)n polymorphism (NPL = 2.77, P = 0.002902). The TDT was significant for (GT)n polymorphism and that the (GT)23 was preferentially transmitted to schizophrenia-affected children (T/NT: 123:72, χ 2 = 13.34, P = 0.000260). Our results indicate that the (GT)n polymorphism in the promoter of GRIN2A gene may play a significant role in the etiology of schizophrenia among our samples.

Identification of a Novel Locus for Febrile Seizures and Epilepsy on Chromosome 21q22

To report results of linkage analysis in a large family with autosomal dominant (AD) febrile seizures (FS) and epilepsy. AD FS and epilepsy is clinically and genetically a heterogeneous group of epilepsies, frequently inherited. The most notable, generalized epilepsy with febrile seizures plus (GEFS+), is characterized by heterogeneous phenotypes including FS persisting beyond the usual age of remission or coexisting with afebrile seizures. Mutations in three subunits of sodium channel genes and one GABA(A)-receptor subunit gene have been identified in some GEFS+ pedigrees. Six genetic loci for FS have been reported so far, but the molecular basis of FS remains unknown. We identified a five-generation family with 13 individuals affected by FS. Evidence was found for coexisting afebrile seizures in some affected individuals. Evaluation included a detailed history and neurologic examination, as well as collection of DNA. After excluding previously identified loci associated with FS and epilepsy, a genome-wide search was performed. Two affected individuals reported only a single FS, whereas the other affected individuals had a history of repeated FS. Coexisting afebrile seizures developed in three individuals. The mode of inheritance was consistent with AD inheritance with an incomplete penetrance. Tight linkage to a group of markers on chromosome 21q22 was identified with flanking markers D21S1909 and D21S1444, and maximum 2-point lod score 3.35 for markers D21S1910 and D21S1894. We excluded four ion-channel genes within this 6.5-cM locus as a cause of FS and epilepsy in this family. We report a novel locus on chromosome 21q22 for AD FS. Identification of the gene causing epilepsy on chromosome 21q22 will advance our understanding of inherited epilepsy and FS, and possibly other types of epilepsies.

No Association of Single Nucleotide Polymorphisms in the μ‐Opioid Receptor Subunit Gene with Idiopathic Generalized Epilepsy

We have investigated the reported association (p = 0.019) between the A118G single nucleotide polymorphism (SNP) of the opioid receptor micro subunit gene (OPRM1) and idiopathic absence epilepsy (IAE). Five SNPs, including A118G, were investigated by association studies in a sample of 240 probands with idiopathic generalized epilepsy (IGE), including 110 with IAE, and 257 controls. No significant association was found for A118G with IGE or IAE. The difference between the two studies was in the control samples that had significantly different allele frequencies (p = 0.00005), suggesting that population stratification may explain the earlier significant association with IAE. In the current study, none of the other four SNPs was significantly associated with IGE or IAE. Our results provide no support for association of A118G with either IAE or IGE and also exclude association in our sample of a small-to-moderate gene effect with IGE from a large part of OPRM1.

Episodic Memory Performance Predicted by the 2bp Deletion in Exon 6 of the “Alpha 7-Like” Nicotinic Receptor Subunit Gene

There is evidence of linkage between chromosome 15q14 and the P50 auditory evoked response, a heritable neuropsychological marker associated with increased risk of schizophrenia. Chromosome 15q14 harbors the alpha-7 nicotinic receptor subunit gene (CHRNA7) and a hybrid gene of unknown function (CHRFAM7A). CHRNA7 is involved in memory formation, a core dysfunction in schizophrenia. The authors set out to determine if this locus is associated with memory dysfunction in schizophrenia.A 2bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene and has previously been associated with P50 deficit, was genotyped in 251 individuals from the Maudsley Family Study of schizophrenia. Episodic memory function was assessed using the Wechsler Memory Scale.Significant associations were identified with delayed recall and percentage retained, with the presence of the deletion predicting worse performance.These observations indicate that episodic memory function is a schizophrenia endophenotype and implicate the CHRFAM7A/CHRNA7 locus in modulating its function.

Episodic Memory Performance Predicted by the 2bp Deletion in Exon 6 of the “Alpha 7-Like” Nicotinic Receptor Subunit Gene

There is evidence of linkage between chromosome 15q14 and the P50 auditory evoked response, a heritable neuropsychological marker associated with increased risk of schizophrenia. Chromosome 15q14 harbors the alpha-7 nicotinic receptor subunit gene (CHRNA7) and a hybrid gene of unknown function (CHRFAM7A). CHRNA7 is involved in memory formation, a core dysfunction in schizophrenia. The authors set out to determine if this locus is associated with memory dysfunction in schizophrenia. A 2bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene and has previously been associated with P50 deficit, was genotyped in 251 individuals from the Maudsley Family Study of schizophrenia. Episodic memory function was assessed using the Wechsler Memory Scale. Significant associations were identified with delayed recall and percentage retained, with the presence of the deletion predicting worse performance. These observations indicate that episodic memory function is a schizophrenia endophenotype and implicate the CHRFAM7A/CHRNA7 locus in modulating its function.

Association of the glutamate receptor subunit gene GRIN2B with attention‐deficit/hyperactivity disorder

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

γ-Aminobutyric Acid Type A Receptors and Alcoholism

Alcohol facilitates gamma-aminobutyric acid (GABA) function, and GABA type A (GABA(A)) receptor-facilitating agents suppress alcohol withdrawal symptoms. Advances in molecular neuroscience, genetics, and neuroimaging provide new insights into the role of brain GABA systems in short- and long-term alcohol effects. To review the role of brain GABA systems in alcohol response, alcohol dependence, alcoholism vulnerability, and alcoholism pharmacotherapy. Literature review. Alcohol increases GABA release, raises neurosteroid levels, and may potently enhance the function of a GABA(A) receptor subclass that shows high affinity for GABA and neurosteroids, relative insensitivity to benzodiazepines, low chloride conductance, and an extrasynaptic location. Variation in GABA(A) receptor subunit genes may contribute to the vulnerability to alcoholism, particularly in the context of environmental risk factors. Alcohol dependence is associated with time-dependent changes in brain GABA(A) receptor density and subunit gene expression levels that contribute to a withdrawal-related deficit in GABA(A) receptor function. However, cortical GABA levels are not reduced during acute withdrawal. Benzodiazepine-assisted detoxification enhances a phasic component of GABA function. However, novel treatments target the tonic component of GABA neurotransmission mediated by benzodiazepine-insensitive GABA(A) receptors. Smoking attenuates withdrawal-related disturbances in brain GABA function, perhaps contributing to comorbid nicotine and alcohol dependence. The GABA systems show recovery with long-term sobriety. Recent research deepens our understanding of the role of GABA systems in alcohol action, alcohol dependence, and the vulnerability to alcoholism. Also, GABA(A) receptor subtype-selective treatments merit exploration for reducing withdrawal symptoms and drinking in alcohol-dependent individuals.

Subplate Neurons Regulate Maturation of Cortical Inhibition and Outcome of Ocular Dominance Plasticity

Synaptic plasticity during critical periods of development requires intact inhibitory circuitry. We report that subplate neurons are needed both for maturation of inhibition and for the proper sign of ocular dominance (OD) plasticity. Removal of subplate neurons prevents the developmental upregulation of genes involved in mature, fast GABAergic transmission in cortical layer 4, including GABA receptor subunits and KCC2, and thus prevents the switch to a hyperpolarizing effect of GABA. To understand the implications of these changes, a realistic circuit model was formulated. Simulations predicted that without subplate neurons, monocular deprivation (MD) paradoxically favors LGN axons representing the deprived (less active) eye, exactly what was then observed experimentally. Simulations also account for published results showing that OD plasticity requires mature inhibition. Thus, subplate neurons regulate molecular machinery required to establish an adult balance of excitation and inhibition in layer 4, and thereby influence the outcome of OD plasticity.