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. 2018 May 8;115(19):5004-5009.
doi: 10.1073/pnas.1721187115. Epub 2018 Apr 24.

Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum

Junsung Woo  1   2 , Joo Ok Min  3   4 , Dae-Si Kang  3   4 , Yoo Sung Kim  3   4 , Guk Hwa Jung  5 , Hyun Jung Park  6 , Sunpil Kim  1   7 , Heeyoung An  1   7 , Jea Kwon  1   7 , Jeongyeon Kim  1 , Insop Shim  6 , Hyung-Gun Kim  8 , C Justin Lee  9   2   7 , Bo-Eun Yoon  10   4
Affiliations

Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum

Junsung Woo et al. Proc Natl Acad Sci U S A. .

Erratum in

Abstract

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.

Keywords: astrocyte; cerebellum; motor coordination; neuronal excitability; tonic GABA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Suppression of tonic inhibition by genetic deletion of Best1 and enhancement by overexpression of MAOB. (A) Schematic illustration for tonic current recording in cerebellar GCs by whole-cell patch clamp. (B, C, E, and F) Representative traces of tonic current in cerebellar GCs from WT mice (B and E) and Best1 KO mice (Balb/C strain) (C and F). +GABA indicates the adding of 5 μM GABA in the recording solution. (D and G) The magnitude of 50-μM GABAzine-sensitive tonic current as indicated (unpaired t test). (H) Schematic showing doxycycline (Dox)-dependent MAOB overexpression in astrocytes. (I, J, L, and M) Representative traces of tonic current from GFAP-MAOB mice (C57BL/6 strain) in −Dox (I and L) and +Dox (J and M) conditions. +GABA indicates the adding of 5 μM GABA in the recording solution. (K and N) The magnitude of GABAzine-sensitive tonic current as indicated (unpaired t test). Error bars are SEM; *P < 0.05; ***P < 0.001; ns indicates P > 0.05. BG, Bergmann glia; GBZ, GABAzine; GCL, GC layer; IHC, immunohistochemistry; MF, mossy fiber; ML, molecular layer; PCL, PC layer; Rec., recording pipette; rtTA, reverse tetracycline responsive transactivator; TET, tetracycline-responsive promoter.
Fig. 2.
Fig. 2.
Modulating tonic inhibition regulates excitability in GCs, but not in PCs. (A and F) Schematic illustration for measurement of excitability in GCs (A) and PCs (F) by current injection. BG, Bergmann glia; GCL, GC layer; MF, mossy fiber; ML, molecular layer; PCL, PC layer; Rec., recording pipette. (B, D, G, and I) Representative traces of excitatory postsynaptic potentials from WT and Best1 KO mice and GFAP-MAOB mice in −Dox and +Dox conditions. (C, E, H, and J) Summary data of firing frequency in GCs and PCs upon varying the injected current (unpaired t test). Error bars are SEM; *P < 0.05; **P < 0.01.
Fig. 3.
Fig. 3.
Modulating tonic inhibition regulates synaptic transmission at MF-PC and PF-PC synapses. (A and F) Schematic illustration for measurement of excitability in PCs by electrical stimulation (Stim.) of MF (A) and PF (F). BG, Bergmann glia; GCL, GC layer; ML, molecular layer; PCL, PC layer; Rec., recording pipette. (B, D, G, and I) Representative traces of excitatory postsynaptic potentials from WT and Best1 KO mice and GFAP-MAOB mice in −Dox and +Dox conditions (at 50-Hz stimulation). (C, E, H, and J) Summary data of firing frequency in PCs at various stimulation frequencies (unpaired t test). Error bars are SEM; *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 4.
Fig. 4.
Astrocytic GABA regulates synaptic transmission at MF-PC and PF-PC synapses. (A and F) Schematic illustration for measurement of excitability in PCs by electrical stimulation (Stim.) of MF (A) and PF (F). BG, Bergmann glia; GCL, GC layer; ML, molecular layer; PCL, PC layer; Rec., recording pipette. (B, D, G, and I) Representative traces of excitatory postsynaptic potentials from WT and Best1 KO mice with or without treatment of GABAzine (GBZ) (50 μM, at 50-Hz stimulation). Ctrl, control. (C, E, H, and J) Summary data of firing frequency in PCs at various stimulation frequencies (unpaired t test). Error bars are SEM; *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 5.
Fig. 5.
Extracellular GABA level is decreased by genetic deletion of Best1 or MAOB but increased by overexpression of MAOB. (A) Schematic illustration for microdialysis. ACSF, artificial cerebrospinal fluid. (B–D) Extracellular GABA (B), putrescine (C), and glutamate (D) concentration from Best1 KO, MAOB KO, and GFAP-MAOB mice (unpaired t test). Values were normalized to WT for Best1 KO and MAOB KO.
Fig. 6.
Fig. 6.
Motor coordination is enhanced by genetic deletion of Best1 or MAOB but impaired by overexpression of MAOB. (A) Experimental timeline and schematic illustration for rotarod test. (B) Experimental timeline for selegiline treatment and rotarod test. (C–F) Summary graph showing latency to fall during test sessions. Error bars are SEM; *P < 0.05; **P < 0.01; ns indicates P > 0.05. Ctrl, control; Sele., selegiline.
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