Targeted deletion of βIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes

被引:62
作者
Stankewich, Michael C. [1 ]
Gwynn, Babette [3 ]
Ardito, Thomas [1 ]
Ji, Lan [1 ]
Kim, Jung [1 ]
Robledo, Raymond F. [3 ]
Lux, Samuel E. [4 ]
Peters, Luanne L. [3 ]
Morrow, Jon S. [1 ,2 ]
机构
[1] Yale Univ, Dept Pathol, New Haven, CT 06520 USA
[2] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA
[3] Jackson Lab, Bar Harbor, ME 04609 USA
[4] Childrens Hosp, Div Hematol & Oncol, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
cytoskeleton; membrane; spinocerebellar ataxia type 5; excitatory amino acid transporter 4; Purkinje; CEREBELLAR PURKINJE NEURONS; GLUTAMATE TRANSPORTERS; ENDOPLASMIC-RETICULUM; NEOCORTICAL EPILEPSY; GOLGI SPECTRIN; IN-VITRO; ANKYRIN; CELLS; CALPAIN; BRAIN;
D O I
10.1073/pnas.1001522107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The spectrin membrane skeleton controls the disposition of selected membrane channels, receptors, and transporters. In the brain beta III spectrin binds directly to the excitatory amino acid transporter (EAAT4), the glutamate receptor delta, and other proteins. Mutations in beta III spectrin link strongly to human spinocerebellar ataxia type 5 (SCA5), correlating with alterations in EAAT4. We have explored the mechanistic basis of this phenotype by targeted gene disruption of Spnb3. Mice lacking intact beta III spectrin develop normally. By 6 months they display a mild nonprogressive ataxia. By 1 year most Spnb3(-/-) animals develop a myoclonic seizure disorder with significant reductions of EAAT4, EAAT1, GluRd, IP3R, and NCAM140. Other synaptic proteins are normal. The cerebellum displays increased dark Purkinje cells (PC), a thin molecular layer, fewer synapses, a loss of dendritic spines, and a 2-fold expansion of the PC dendrite diameter. Membrane and expanded Golgi profiles fill the PC dendrite and soma, and both regions accumulate EAAT4. Correlating with the seizure disorder are enhanced hippocampal levels of neuropeptide Y and EAAT3 and increased calpain proteolysis of alpha II spectrin. It appears that beta III spectrin disruption impairs synaptogenesis by disturbing the intracellular pathways selectively regulating protein trafficking to the synapse. The mislocalization of these proteins secondarily disrupts glutamate transport dynamics, leading to seizures, neuronal damage, and compensatory changes in EAAT3 and neuropeptide Y.
引用
收藏
页码:6022 / 6027
页数:6
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