Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST.
Clinical phenotypes of spinocerebellar ataxia type-5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1) are mirrored in mice lacking β-III spectrin (β-III-/-). One function of β-III spectrin is the stabilization of the Purkinje cell-specific glutamate transporter EAAT4 at the plasma membrane. In β-III-/- mice EAAT4 levels are reduced from an early age. In contrast levels of the predominant cerebellar glutamate transporter GLAST, expressed in Bergmann glia, only fall progressively from 3 months onwards. Here we elucidated the roles of these two glutamate transporters in cerebellar pathogenesis mediated through loss of β-III spectrin function by studying EAAT4 and GLAST knockout mice as well as crosses of both with β-III-/- mice. Our data demonstrate that EAAT4 loss, but not abnormal AMPA receptor composition, in young β-III-/- mice underlies early Purkinje cell hyper-excitability and that subsequent loss of GLAST, superimposed on the earlier deficiency of EAAT4, is responsible for Purkinje cell loss and progression of motor deficits. Yet the loss of GLAST appears to be independent of EAAT4 loss, highlighting that other aspects of Purkinje cell dysfunction underpin the pathogenic loss of GLAST. Finally, our results demonstrate that Purkinje cells in the posterior cerebellum of β-III-/- mice are most susceptible to the combined loss of EAAT4 and GLAST, with degeneration of proximal dendrites, the site of climbing fibre innervation, most pronounced. This highlights the necessity for efficient glutamate clearance from these regions and identifies dysregulation of glutamatergic neurotransmission particularly within the posterior cerebellum as a key mechanism in SCA5 and SPARCA1 pathogenesis.
The Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
Emma M
EM
Perkins
The Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
Daumante
D
Suminaite
The Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
Yvonne L
YL
Clarkson
The Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
Sin Kwan
SK
Lee
School of Energy, Geoscience, Infrastructure and Society, Heriot-Watt University, John Muir Building, Riccarton, Edinburgh, UK.
Alastair R
AR
Lyndon
Department of Neurology and Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Jeffrey D
JD
Rothstein
The Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India
David J A
DJ
Wyllie
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan.
Kohichi
K
Tanaka
The Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
Mandy
M
Jackson
D000818:Animals; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism* / Q000502:physiology; D050581:Excitatory Amino Acid Transporter 4 / Q000378:metabolism* / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D013049:Spectrin / Q000378:metabolism* / Q000502:physiology; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D027341:Excitatory Amino Acid Transporter 1; D050581:Excitatory Amino Acid Transporter 4; C000595041:SPTBN2 protein, mouse; C493393:Slc1a3 protein, mouse; C493390:Slc1a6 protein, mouse; D013049:Spectrin