Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors

Igor Ponomarev, Rajani Maiya, Mark T. Harnett, Gwen L. Schafer, Andrey Ryabinin, Yuri A. Blednov, Hitoshi Morikawa, Stephen L. Boehm, Gregg E. Homanics, Ari Berman, Kerrie H. Lodowski, Susan E. Bergeson, R. Adron Harris

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 sometranscriptional 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.

Original languageEnglish (US)
Pages (from-to)5673-5683
Number of pages11
JournalJournal of Neuroscience
Volume26
Issue number21
DOIs
StatePublished - 2006

Fingerprint

GABA-A Receptors
Neuronal Plasticity
Synaptic Transmission
Neuroglia
Neurogranin
rac1 GTP-Binding Protein
Genes
Phenotype
Voltage-Gated Potassium Channels
Neurons
Sodium Channels
Dermatoglyphics
Oligonucleotide Array Sequence Analysis
Knockout Mice
Astrocytes
Computer Simulation
Cerebral Cortex
Synapses
Cerebellum
gamma-Aminobutyric Acid

Keywords

  • Gene expression
  • Glia
  • Knock-out
  • Microarray
  • Neuroadaptation
  • Neuron
  • Null mutant
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ponomarev, I., Maiya, R., Harnett, M. T., Schafer, G. L., Ryabinin, A., Blednov, Y. A., ... Adron Harris, R. (2006). Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors. Journal of Neuroscience, 26(21), 5673-5683. https://doi.org/10.1523/JNEUROSCI.0860-06.2006

Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors. / Ponomarev, Igor; Maiya, Rajani; Harnett, Mark T.; Schafer, Gwen L.; Ryabinin, Andrey; Blednov, Yuri A.; Morikawa, Hitoshi; Boehm, Stephen L.; Homanics, Gregg E.; Berman, Ari; Lodowski, Kerrie H.; Bergeson, Susan E.; Adron Harris, R.

In: Journal of Neuroscience, Vol. 26, No. 21, 2006, p. 5673-5683.

Research output: Contribution to journalArticle

Ponomarev, I, Maiya, R, Harnett, MT, Schafer, GL, Ryabinin, A, Blednov, YA, Morikawa, H, Boehm, SL, Homanics, GE, Berman, A, Lodowski, KH, Bergeson, SE & Adron Harris, R 2006, 'Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors', Journal of Neuroscience, vol. 26, no. 21, pp. 5673-5683. https://doi.org/10.1523/JNEUROSCI.0860-06.2006
Ponomarev, Igor ; Maiya, Rajani ; Harnett, Mark T. ; Schafer, Gwen L. ; Ryabinin, Andrey ; Blednov, Yuri A. ; Morikawa, Hitoshi ; Boehm, Stephen L. ; Homanics, Gregg E. ; Berman, Ari ; Lodowski, Kerrie H. ; Bergeson, Susan E. ; Adron Harris, R. / Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 21. pp. 5673-5683.
@article{45df2263be6b4f3687d8fcabf51d5504,
title = "Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors",
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 sometranscriptional 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.",
keywords = "Gene expression, Glia, Knock-out, Microarray, Neuroadaptation, Neuron, Null mutant, Synapse",
author = "Igor Ponomarev and Rajani Maiya and Harnett, {Mark T.} and Schafer, {Gwen L.} and Andrey Ryabinin and Blednov, {Yuri A.} and Hitoshi Morikawa and Boehm, {Stephen L.} and Homanics, {Gregg E.} and Ari Berman and Lodowski, {Kerrie H.} and Bergeson, {Susan E.} and {Adron Harris}, R.",
year = "2006",
doi = "10.1523/JNEUROSCI.0860-06.2006",
language = "English (US)",
volume = "26",
pages = "5673--5683",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "21",

}

TY - JOUR

T1 - Transcriptional signatures of cellular plasticity in mice lacking the α1 subunit of GABAA receptors

AU - Ponomarev, Igor

AU - Maiya, Rajani

AU - Harnett, Mark T.

AU - Schafer, Gwen L.

AU - Ryabinin, Andrey

AU - Blednov, Yuri A.

AU - Morikawa, Hitoshi

AU - Boehm, Stephen L.

AU - Homanics, Gregg E.

AU - Berman, Ari

AU - Lodowski, Kerrie H.

AU - Bergeson, Susan E.

AU - Adron Harris, R.

PY - 2006

Y1 - 2006

N2 - 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 sometranscriptional 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.

AB - 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 sometranscriptional 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.

KW - Gene expression

KW - Glia

KW - Knock-out

KW - Microarray

KW - Neuroadaptation

KW - Neuron

KW - Null mutant

KW - Synapse

UR - http://www.scopus.com/inward/record.url?scp=33744968446&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33744968446&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0860-06.2006

DO - 10.1523/JNEUROSCI.0860-06.2006

M3 - Article

VL - 26

SP - 5673

EP - 5683

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 21

ER -