Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABAA Receptors

Published on May 24, 2006in The Journal of Neuroscience6.167
· DOI :10.1523/JNEUROSCI.0860-06.2006
Igor Ponomarev22
Estimated H-index: 22
(University of Texas at Austin),
Rajani Maiya13
Estimated H-index: 13
(University of Texas at Austin)
+ 10 AuthorsR. Adron Harris77
Estimated H-index: 77
(University of Texas at Austin)
Sources
Abstract
GABAA receptors mediate the majority of inhibitory neurotransmission in the CNS. Genetic deletion of the α1 subunit of GABAA receptors results in a loss of α1-mediated fast inhibitory currents and a marked reduction in density of GABAA receptors. A grossly normal phenotype of α1-deficient mice suggests the presence of neuronal adaptation to these drastic changes at the GABA synapse. We used cDNA microarrays to identify transcriptional fingerprints of cellular plasticity in response to altered GABAergic inhibition in the cerebral cortex and cerebellum of α1 mutants. In silico analysis of 982 mutation-regulated transcripts highlighted genes and functional groups involved in regulation of neuronal excitability and synaptic transmission, suggesting an adaptive response of the brain to an altered inhibitory tone. Public gene expression databases permitted identification of subsets of transcripts enriched in excitatory and inhibitory neurons as well as some glial cells, providing evidence for cellular plasticity in individual cell types. Additional analysis linked some transcriptional changes to cellular phenotypes observed in the knock-out mice and suggested several genes, such as the early growth response 1 (Egr1), small GTP binding protein Rac1 (Rac1), neurogranin (Nrgn), sodium channel β4 subunit (Scn4b), and potassium voltage-gated Kv4.2 channel (Kcnd2) as cell type-specific markers of neuronal plasticity. Furthermore, transcriptional activation of genes enriched in Bergman glia suggests an active role of these astrocytes in synaptic plasticity. Overall, our results suggest that the loss of α1-mediated fast inhibition produces diverse transcriptional responses that act to regulate neuronal excitability of individual neurons and stabilize neuronal networks, which may account for the lack of severe abnormalities in α1 null mutants.
📖 Papers frequently viewed together
20003.59Neuroscience
5 Authors (Susanne Pirker, ..., Günther Sperk)
References68
Newest
#1Jason E. Kralic (UZH: University of Zurich)H-Index: 15
#2Corinne Sidler (UZH: University of Zurich)H-Index: 10
Last. Jean-Marc Fritschy (UZH: University of Zurich)H-Index: 110
view all 6 authors...
Targeted deletion of the α1 subunit gene results in a profound loss of γ-aminobutyric acid type A (GABAA) receptors in adult mouse brain but has only moderate behavioral consequences. Mutant mice exhibit several adaptations in GABAA receptor subunit expression, as measured by Western blotting. By using immunohistochemistry, we investigated here whether these adaptations serve to replace the missing α1 subunit or represent compensatory changes in neurons that normally express these subunits. We f...
Source
#1Jianyuan Sun (UTSW: University of Texas Southwestern Medical Center)H-Index: 12
#2Peter BronkH-Index: 3
Last. Thomas C. SüdhofH-Index: 214
view all 5 authors...
Synapsins are abundant synaptic-vesicle phosphoproteins that are known to regulate neurotransmitter release but whose precise function has been difficult to pinpoint. Here, we use knockout mice to analyze the role of synapsins 1 and 2 in the calyx of Held synapse, allowing precise measurements of neurotransmitter release. We find that deletion of synapsins did not induce significant changes in spontaneous release or release evoked by isolated action potentials (APs) and did not alter the size of...
Source
#1Waltraud OgrisH-Index: 5
#2Reinhard LehnerH-Index: 4
Last. Werner SieghartH-Index: 88
view all 7 authors...
In cerebellum, 75% of all GABAA receptors contain a1 subunits. Here, we investigated compensatory changes in GABAA receptor subunit expression and composition in a1 subunitknockout mice. In these mice the total number of cerebellar GABAA receptors was reduced by 46%. Whereas the number of receptors containing a6 subunits was unchanged, the total amount of a6 subunits was significantly elevated. RT-PCR showed no increase of a6 mRNA levels, arguing against increased biosynthesis of these subunits....
Source
#1Ken Sugino (Brandeis University)H-Index: 27
#2Chris M. Hempel (Brandeis University)H-Index: 12
Last. Sacha B. Nelson (Brandeis University)H-Index: 72
view all 8 authors...
Identifying the neuronal cell types that comprise the mammalian forebrain is a central unsolved problem in neuroscience. Global gene expression profiles offer a potentially unbiased way to assess functional relationships between neurons. Here, we carried out microarray analysis of 12 populations of neurons in the adult mouse forebrain. Five of these populations were chosen from cingulate cortex and included several subtypes of GABAergic interneurons and pyramidal neurons. The remaining seven wer...
Source
#1Andreas Papassotiropoulos (UZH: University of Zurich)H-Index: 65
#2M. Axel Wollmer (UZH: University of Zurich)H-Index: 19
Last. Dominique J.-F. de Quervain (UZH: University of Zurich)H-Index: 59
view all 6 authors...
Human cognitive processes are highly variable across individuals and are influenced by both genetic and environmental factors. Although genetic variations affect short-term memory in humans, it is unknown whether genetic variability has also an impact on long-term memory. Because prion-like conformational changes may be involved in the induction of long-lasting synaptic plasticity, we examined the impact of single-nucleotide polymorphisms (SNPs) of the prion protein gene (PRNP) on long-term memo...
Source
#1Michael Beierlein (Harvard University)H-Index: 23
#2Wade G. Regehr (Harvard University)H-Index: 79
Powerful synapses between climbing fibers (CF) and Purkinje cells are crucial to cerebellar motor learning. In this issue of Neuron, Lin and colleagues provide compelling evidence for the existence of direct synaptic contacts between CFs and NG2-expressing glia cells, adding to the intrigue of neuro-glial interactions.
Source
#1Brian W. Strassle (Princeton University)H-Index: 12
#2Milena Menegola (UC Davis: University of California, Davis)H-Index: 8
Last. James S. Trimmer (UC Davis: University of California, Davis)H-Index: 87
view all 4 authors...
Potassium channels are key determinants of neuronal excitability. We recently identified KChIPs as a family of calcium binding proteins that coassociate and colocalize with Kv4 family potassium channels in mammalian brain (An et al. [2000] Nature 403:553). Here, we used light microscopic immunohistochemistry and multilabel immunofluorescence labeling, together with transmission electron microscopic immunohistochemistry, to examine the subcellular distribution of KChIPs and Kv4 channels in adult ...
Source
#1Laurens W.J. Bosman (VU: VU University Amsterdam)H-Index: 17
#2Klaartje HeinenH-Index: 1
Last. Arjen B. BrussaardH-Index: 35
view all 4 authors...
There is a large variation in structurally and functionally different GABAA receptor subtypes. The expression pattern of GABAA receptor subunits is highly regulated, both temporarily and spatially. Especially during development, profound changes in subunit expression have been described. In most brain areas, the GABAA receptor α1 subunit replaces the α2 and/or α3 subunit as major α subunit. This is accompanied by a marked decrease in the open time of GABAA receptors and hence in the duration of ...
Source
#1Jason E. Kralic (UNC: University of North Carolina at Chapel Hill)H-Index: 15
#2Hugh E. Criswell (UNC: University of North Carolina at Chapel Hill)H-Index: 40
Last. A. Leslie Morrow (UNC: University of North Carolina at Chapel Hill)H-Index: 59
view all 10 authors...
Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that γ-aminobutyric acidA (GABAA) receptor α1–/– mice exhibit postural and kinetic tremor and motor incoordination that is characteristic of essential tremor disease. We tested mice with essential-like tremor using current drug therapies that alleviate symptoms in essential tremor patients (primidone, propranolol, and gabapentin) and several candidates hypothesized to reduce tremor, including ethano...
Source
#1Elissa J. Chesler (UTHSC: University of Tennessee Health Science Center)H-Index: 59
#2Lu Lu (UTHSC: University of Tennessee Health Science Center)H-Index: 45
Last. Robert W. Williams (UTHSC: University of Tennessee Health Science Center)H-Index: 85
view all 13 authors...
Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred s...
Source
Cited By55
Newest
#1Brent R. KisbyH-Index: 1
#2Sean P. FarrisH-Index: 14
Last. Igor Ponomarev (TTUHSC: Texas Tech University Health Sciences Center)H-Index: 2
view all 7 authors...
Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chroni...
Source
#1Calvin W. Daack (Drake University)
#2Derek Yeh (Drake University)
Last. Christopher L. Kliethermes (Drake University)H-Index: 3
view all 4 authors...
Ethanol at low doses induces a locomotor stimulant response across a range of phylogenetically diverse species. In rodents, this response is commonly used as an index of ethanol's disinhibitory, anxiolytic, or reinforcing effects, and its expression is regulated by signaling through a number of conserved neurotransmitter systems. In the current experiments, we asked whether ethanol-induced locomotor stimulation in the fruit fly Drosophila melanogaster might be mediated by ionotropic GABA recepto...
Source
#1Júlia Canet-Pons (Goethe University Frankfurt)H-Index: 5
#2Nesli-Ece Sen (Goethe University Frankfurt)H-Index: 9
Last. Georg Auburger (Goethe University Frankfurt)H-Index: 72
view all 18 authors...
Abstract: Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. ...
Source
#1Christopher M. Davenport (University of California, Berkeley)H-Index: 13
#2Rajit Rajappa (University of California, Berkeley)H-Index: 6
Last. Richard H. Kramer (University of California, Berkeley)H-Index: 45
view all 10 authors...
Summary The excitatory synapse between hippocampal CA3 and CA1 pyramidal neurons exhibits long-term potentiation (LTP), a positive feedback process implicated in learning and memory in which postsynaptic depolarization strengthens synapses, promoting further depolarization. Without mechanisms for interrupting positive feedback, excitatory synapses could strengthen inexorably, corrupting memory storage. Here, we reveal a hidden form of inhibitory synaptic plasticity that prevents accumulation of ...
Source
#1Mari A. VirtanenH-Index: 7
#2Pavel UvarovH-Index: 16
Last. Kai KailaH-Index: 83
view all 4 authors...
Ionotropic GABA transmission is mediated by anion (mainly Cl−)-permeable GABAA receptors (GABAARs). In immature neurons, GABA exerts depolarizing and sometimes functionally excitatory actions, based on active uptake of Cl− by the Na-K-2Cl cotransporter NKCC1. While functional evidence firmly shows NKCC1-mediated ion transport in immature and diseased neurons, molecular detection of NKCC1 in the brain has turned out to be extremely difficult. In this review, we describe the highly inconsistent da...
Source
#1Júlia Canet-Pons (Goethe University Frankfurt)H-Index: 5
#2Nesli-Ece Sen (Goethe University Frankfurt)H-Index: 9
Last. Georg Auburger (Goethe University Frankfurt)H-Index: 72
view all 18 authors...
Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we e...
Source
#2Matthew Brooks (NIH: National Institutes of Health)H-Index: 33
Last. Tudor C. BadeaH-Index: 27
view all 3 authors...
Background About 20–30 distinct Retinal Ganglion Cell (RGC) types transmit visual information from the retina to the brain. The developmental mechanisms by which RGCs are specified are still largely unknown. Brn3a is a member of the Brn3/Pou4f transcription factor family, which contains key regulators of RGC postmitotic specification. In particular, Brn3a ablation results in the loss of RGCs with small, thick and dense dendritic arbors (‘midget-like’ RGCs), and morphological changes in other RGC...
Source
#1John Peyton Bohnsack (UIC: University of Illinois at Chicago)H-Index: 9
#2Benjamin A. Hughes (UNC: University of North Carolina at Chapel Hill)H-Index: 3
Last. A. Leslie Morrow (UNC: University of North Carolina at Chapel Hill)H-Index: 59
view all 6 authors...
Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAAR) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAAR hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still un...
Source
#1Marta Valenza (BU: Boston University)H-Index: 14
#2Alyssa DiLeo (BU: Boston University)H-Index: 5
Last. Valentina Sabino (BU: Boston University)H-Index: 32
view all 5 authors...
Abstract Rationale The Sigma-1 receptor (Sig-1R) is a chaperone protein that has been implicated in drug abuse and addiction. Multiple studies have characterized the role the Sig-1R plays in psychostimulant addiction; however, fewer studies have specifically investigated its role in alcohol addiction. We have previously shown that antagonism of the Sig-1R reduces excessive drinking and motivation to drink, whereas agonism induces binge-like drinking in rodents. Objectives The objectives of these...
Source
#1Wan-Chen Lin (University of California, Berkeley)H-Index: 6
#2Ming-Chi Tsai (University of California, Berkeley)H-Index: 8
Last. Richard H. Kramer (HWNI: Helen Wills Neuroscience Institute)H-Index: 45
view all 8 authors...
Summary Exogenously expressed opsins are valuable tools for optogenetic control of neurons in circuits. A deeper understanding of neural function can be gained by bringing control to endogenous neurotransmitter receptors that mediate synaptic transmission. Here we introduce a comprehensive optogenetic toolkit for controlling GABA A receptor-mediated inhibition in the brain. We developed a series of photoswitch ligands and the complementary genetically modified GABA A receptor subunits. By conjug...
Source
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.