Open AccessTargeted deletion of βIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes
Author(s) -
Michael C. Stankewich,
Babette Gwynn,
Thomas Ardito,
Jing Lan,
Jung Kim,
Raymond F. Robledo,
Samuel E. Lux,
Luanne L. Peters,
Jon S. Morrow
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1001522107
Subject(s) - spectrin , synaptogenesis , microbiology and biotechnology , ankyrin , biology , ampa receptor , dendritic spine , cerebellum , purkinje cell , spinocerebellar ataxia , glutamate receptor , neuroscience , receptor , hippocampal formation , ataxia , biochemistry , cytoskeleton , gene , cell
The spectrin membrane skeleton controls the disposition of selected membrane channels, receptors, and transporters. In the brain βIII spectrin binds directly to the excitatory amino acid transporter (EAAT4), the glutamate receptor delta, and other proteins. Mutations in βIII 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 ofSpnb3 . Mice lacking intact βIII spectrin develop normally. By 6 months they display a mild nonprogressive ataxia. By 1 year mostSpnb3 −/− animals develop a myoclonic seizure disorder with significant reductions of EAAT4, EAAT1, GluRδ, 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 αII spectrin. It appears that βIII 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.