Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABAAReceptor γ2 Subunit in the Cerebellum.
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAAreceptors. 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 GABAAreceptors 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 GABAAreceptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAAreceptor 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 GABAAresponses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAAreceptors 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 GABAAreceptors 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.
Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland.
Elli
E
Leppä
Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland.
Anni-Maija
AM
Linden
Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández de Elche San Juan de Alicante, Spain.
Maria I
MI
Aller
Institute of Physiology, University of Kiel Kiel, Germany.
Peer
P
Wulff
Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland.
Olga
O
Vekovischeva
Department of Biology, The Pennsylvania State University University Park, PA, USA.
Bernhard
B
Luscher
Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz Mainz, Germany.
Hartmut
H
Lüddens
Department of Life Sciences, Imperial College London London, UK.
William
W
Wisden
Department of Pharmacology, Faculty of Medicine, University of Helsinki Helsinki, Finland.
Esa R
ER
Korpi
Purkinje cells; cerebellum; extrasynaptic GABAA receptors; motor performance; neurosteroids