title: Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3-deficient heterozygous mice.
abstract: Dystonia is characterized by excessive involuntary and prolonged simultaneous contractions of both agonist and antagonist muscles. Although the basal ganglia have long been proposed as the primary region, recent studies indicated that the cerebellum also plays a key role in the expression of dystonia. One hereditary form of dystonia, rapid-onset dystonia with parkinsonism (RDP), is caused by loss of function mutations of the gene for the Na pump α3 subunit (ATP1A3). Little information is available on the affected brain regions and mechanism for dystonia by the mutations in RDP. The Na pump is composed of α and β subunits and maintains ionic gradients of Na(+) and K(+) across the cell membrane. The gradients are utilized for neurotransmitter reuptake and their alteration modulates neural excitability. To provide insight into the molecular aetiology of RDP, we generated and analysed knockout heterozygous mice (Atp1a3(+/-)). Atp1a3(+/-) showed increased symptoms of dystonia that is induced by kainate injection into the cerebellar vermis. Atp1a3 mRNA was highly expressed in Purkinje cells and molecular-layer interneurons, and its product was concentrated at Purkinje cell soma, the site of abundant vesicular γ-aminobutyric acid transporter (VGAT) signal, suggesting the presynaptic localization of the α3 subunit in the inhibitory synapse. Electrophysiological studies showed that the inhibitory neurotransmission at molecular-layer interneuron-Purkinje cell synapses was enhanced in Atp1a3(+/-) cerebellar cortex, and that the enhancement originated via a presynaptic mechanism. Our results shed light on the role of Atp1a3 in the inhibitory synapse, and potential involvement of inhibitory synaptic dysfunction for the pathophysiology of dystonia.
authors: Division of Biology, Center for Molecular Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan. kiikeda@hyo-med.ac.jp
authors: Keiko
authors: K
authors: Ikeda
authors: Shin'Ichiro
authors: S
authors: Satake
authors: Tatsushi
authors: T
authors: Onaka
authors: Hiroki
authors: H
authors: Sugimoto
authors: Naoki
authors: N
authors: Takeda
authors: Keiji
authors: K
authors: Imoto
authors: Kiyoshi
authors: K
authors: Kawakami
mesh_terms: D000818:Animals; D002525:Cerebellar Cortex / Q000502:physiology*; D004421:Dystonia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009474:Neurons / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology; D011597:Psychomotor Performance; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D021122:Protein Subunits; C526097:Atp1a3 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase
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