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Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice.

ABSTRACT: ?-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian central nervous system and plays modulatory roles in neural development. The vesicular GABA transporter (VGAT) is an essential molecule for GABAergic neurotransmission due to its role in vesicular GABA release. Cerebellar Purkinje cells (PCs) are GABAergic projection neurons that are indispensable for cerebellar function. To elucidate the significance of VGAT in cerebellar PCs, we generated and characterized PC-specific VGAT knockout (L7-VGAT) mice. VGAT mRNAs and proteins were specifically absent in the 40-week-old L7-VGAT PCs. The morphological characteristics, such as lamination and foliation of the cerebellar cortex, of the L7-VGAT mice were similar to those of the control littermate mice. Moreover, the protein expression levels and patterns of pre- (calbindin and parvalbumin) and postsynaptic (GABA-A receptor ?1 subunit and gephyrin) molecules between the L7-VGAT and control mice were similar in the deep cerebellar nuclei that receive PC projections. However, the L7-VGAT mice performed poorly in the accelerating rotarod test and displayed ataxic gait in the footprint test. The L7-VGAT mice also exhibited severer ataxia as VGAT deficits progressed. These results suggest that VGAT in cerebellar PCs is not essential for the rough maintenance of cerebellar structure, but does play an important role in motor coordination. The L7-VGAT mice are a novel model of ataxia without PC degeneration, and would also be useful for studying the role of PCs in cognition and emotion.

SUBMITTER: Kayakabe M

PROVIDER: S-EPMC3893617 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice.

Kayakabe Mikiko M Kakizaki Toshikazu T Kaneko Ryosuke R Sasaki Atsushi A Nakazato Yoichi Y Shibasaki Koji K Ishizaki Yasuki Y Saito Hiromitsu H Suzuki Noboru N Furuya Nobuhiko N Yanagawa Yuchio Y

Frontiers in cellular neuroscience 20140116

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian central nervous system and plays modulatory roles in neural development. The vesicular GABA transporter (VGAT) is an essential molecule for GABAergic neurotransmission due to its role in vesicular GABA release. Cerebellar Purkinje cells (PCs) are GABAergic projection neurons that are indispensable for cerebellar function. To elucidate the significance of VGAT in cerebellar PCs, we generated and characterized ...[more]

PMID: 24474904

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Project description:Hormones and nuclear receptors (NRs) play important roles in brain development and function. The recently identified steroid receptor coactivator (SRC) family contains three homologous members that can enhance transcriptional activities of NRs and certain non-NR transcription factors. To study the role of SRC-1 in brain development and function, we examined the spatial and temporal expression patterns of SRC-1 and characterized the phenotypes of brain development and function in SRC-1 knock-out (SRC-1(-)/-) mice. In the adult mouse brain, SRC-1 is highly expressed in the olfactory bulb, hippocampus, piriform cortex, amygdala, hypothalamus, cerebellum, and brainstem. Multiple behavioral tests revealed that SRC-1(-)/- mice exhibit normal hippocampal function but moderate motor dysfunction. The behavior phenotypes correlate with the spatial distribution of the SRC family members. In most brain structures where SRC-1 is expressed, SRC-2 is expressed at lower levels; however, SRC-3 mRNA is detectable only in the hippocampus. In the adult cerebellum, Purkinje cells (PCs) preferentially express SRC-1 over SRC-2, but SRC-2 mRNA is slightly elevated in the SRC-1(-)/- PCs. During embryonic development, SRC-1 is expressed in the cerebellar primordium. SRC-2 is expressed in PCs after postnatal day (P) 10. Time course analysis revealed that the precursors of SRC-1(-)/- PCs were generated approximately 2 d later than wild-type precursor cells. A further delay in SRC-1(-)/- PC maturation was detected at the neonatal stage. The morphology and number of SRC-1(-)/- PCs were equivalent to wild type by P10; this timing correlated with the early expression of SRC-2 in the SRC-1(-)/- PCs. These results demonstrate that the relative levels of SRC expression are region specific, and the degree of overlapping expression may influence their functional redundancy. Disruption of SRC-1 specifically delays the PC development and maturation in early stages and results in moderate motor dysfunction in adulthood.

Dataset Information

Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice.

Publications

Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice.

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