Increased motor-impairing effects of the neuroactive steroid pregnanolone in mice with targeted inactivation of the GABAA receptor γ2 subunit in the cerebellum

Elli Leppä, Anni Maija Linden, Maria I. Aller, Peer Wulff, Olga Vekovischeva, Bernhard Luscher, Hartmut Lüddens, William Wisden, Esa R. Korpi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior.

Original languageEnglish (US)
Article number403
JournalFrontiers in Pharmacology
Volume7
Issue numberOCT
DOIs
StatePublished - Oct 27 2016

Fingerprint

Pregnanolone
GABA-A Receptors
Cerebellum
Purkinje Cells
Steroids
Parvalbumins
Neurotransmitter Receptor
Genetic Models
Anti-Anxiety Agents
Population
Neurotransmitter Agents
Neurons
Light
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Leppä, Elli ; Linden, Anni Maija ; Aller, Maria I. ; Wulff, Peer ; Vekovischeva, Olga ; Luscher, Bernhard ; Lüddens, Hartmut ; Wisden, William ; Korpi, Esa R. / Increased motor-impairing effects of the neuroactive steroid pregnanolone in mice with targeted inactivation of the GABAA receptor γ2 subunit in the cerebellum. In: Frontiers in Pharmacology. 2016 ; Vol. 7, No. OCT.
@article{0fe518b02d364e92bec211d377a1e01d,
title = "Increased motor-impairing effects of the neuroactive steroid pregnanolone in mice with targeted inactivation of the GABAA receptor γ2 subunit in the cerebellum",
abstract = "Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior.",
author = "Elli Lepp{\"a} and Linden, {Anni Maija} and Aller, {Maria I.} and Peer Wulff and Olga Vekovischeva and Bernhard Luscher and Hartmut L{\"u}ddens and William Wisden and Korpi, {Esa R.}",
year = "2016",
month = "10",
day = "27",
doi = "10.3389/fphar.2016.00403",
language = "English (US)",
volume = "7",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media S. A.",
number = "OCT",

}

Increased motor-impairing effects of the neuroactive steroid pregnanolone in mice with targeted inactivation of the GABAA receptor γ2 subunit in the cerebellum. / Leppä, Elli; Linden, Anni Maija; Aller, Maria I.; Wulff, Peer; Vekovischeva, Olga; Luscher, Bernhard; Lüddens, Hartmut; Wisden, William; Korpi, Esa R.

In: Frontiers in Pharmacology, Vol. 7, No. OCT, 403, 27.10.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased motor-impairing effects of the neuroactive steroid pregnanolone in mice with targeted inactivation of the GABAA receptor γ2 subunit in the cerebellum

AU - Leppä, Elli

AU - Linden, Anni Maija

AU - Aller, Maria I.

AU - Wulff, Peer

AU - Vekovischeva, Olga

AU - Luscher, Bernhard

AU - Lüddens, Hartmut

AU - Wisden, William

AU - Korpi, Esa R.

PY - 2016/10/27

Y1 - 2016/10/27

N2 - Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior.

AB - Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior.

UR - http://www.scopus.com/inward/record.url?scp=84995503997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995503997&partnerID=8YFLogxK

U2 - 10.3389/fphar.2016.00403

DO - 10.3389/fphar.2016.00403

M3 - Article

AN - SCOPUS:84995503997

VL - 7

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

IS - OCT

M1 - 403

ER -