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Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats
被引:39
作者:
Hampe, Christiane S.
[1
]
Petrosini, Laura
[2
,3
]
De Bartolo, Paola
[2
,3
]
Caporali, Paola
Cutuli, Debora
[2
,3
]
Laricchiuta, Daniela
Foti, Francesca
[2
,4
]
Radtke, Jared R.
[1
]
Vidova, Veronika
[1
]
Honnorat, Jerome
[5
]
Manto, Mario
[6
]
机构:
[1] Univ Washington, Sch Med, Seattle, WA 98109 USA
[2] IRCCS, Santa Lucia Fdn, Rome, Italy
[3] Univ Roma La Sapienza, Dept Psychol, Rome, Italy
[4] Univ Roma La Sapienza, Dept Dev & Social Psychol, Rome, Italy
[5] Univ Lyon 1, Hosp Civils Lyon, Ctr Reference Diagnost & Traitement Syndromes Neu, Lyon Neurosci Res Ctr INSERM CNRS UMR U1082 5292, Lyon, France
[6] ULB Erasme, FNRS Neurol, Unite Etud Mouvement, Brussels, Belgium
基金:
美国国家卫生研究院;
关键词:
Glutamate decarboxylase;
Monoclonal antibodies;
Morris Water Maze;
Neurological;
Evaluation;
STIFF-PERSON-SYNDROME;
CEREBELLAR PURKINJE-CELLS;
MORRIS WATER MAZE;
SV40 LARGE T;
NITRIC-OXIDE;
AUTOANTIBODIES;
ATAXIA;
IMPAIRMENT;
DIFFERENTIATION;
INHIBITION;
D O I:
10.1186/1750-1172-8-82
中图分类号:
Q3 [遗传学];
学科分类号:
071007 ;
090102 ;
摘要:
Background: Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78). Methods: Rats received three injections of GAD65Ab b96.11 (5 or 7 mu g), GAD65Ab b78 (5 or 7 mu g), or saline at the level of three cerebellar nuclei. Animals were submitted to neurological evaluation and Morris Water Maze (MWM) test. Cellular internalization of GAD65Ab was analyzed by Flow Cytometry, Fluorescence and Bright Field microscopy. Results: Monoclonal GAD65Ab induced dose-dependent and epitope-specific effects on motor and cognitive functions. Injections of the higher dose altered motor and spatial procedural behaviors, while the lower dose induced only modest cerebellar motor symptoms and did not affect MWM performances. While b96.11 provoked immediate severe effects, which rapidly decreased, b78 induced moderate but prolonged effects. Both GAD65Ab were taken up by live cells in a dose-dependent manner. Conclusions: Our findings support the hypothesis that epitope-specific GAD65Ab induce cerebellar dysfunction impairing motor and procedural abilities. This is the first demonstration of a critical role of cerebellar nuclei GAD65 enzyme in procedural spatial functions.
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