| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2001: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2000: ¥9,100,000 (Direct Cost: ¥9,100,000)
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| Research Abstract |
We discovered new autoantibodies against a metabotropic glutamate receptor, mGluR1, in two patients of Hodgkin s disease with paraneoplastic cerebellar ataxia. These antibodies blocked activation of mGluR1 in vitro and, after injection into subarachnoidal space of mouse cerebellum, caused reversible ataxia, reproducing symptoms observed in the patients. To further screen autoantibodies to functional membrane molecules including mGluR1, more than one hundred serum and cerebrospinal fluid were tested with immunostaining of rat brain sections and cells expressing mGluR1. Unfortunately, no more cases with anti-mGIuR1 autoantibodies were found but some of the samples gave immunostaining of Purkinje cells typical for Tr antibody. In addition, one of the screened antiserum specifically reacted with parvalbumin-positive interneurons in the cerebral cortex. The target molecule for this antibody is now under investigation.
To understand physiological role of mGluR1,.we used the mGluR1-blocking au
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toantibody for disturbing mGluR1 function in the mouse cerebellum and monkey globus pallidus. In the mouse cerebellum, injection of the autoantibody caused impaired adaptation of vestibulo-ocular reflex (VOR), indicating that activation of mGluR1 is necessary for this type of motor learning. Consistent with this finding, long-term depression qf AMPA sensitivity of cultured Purkinje cells was blocked by the autoantibody. Also, in slice preparation, this antibody blocked inward current caused by mGluR1 agonist DHPG, and elicited a slow outward current in whole cell clamped Purkinje cells. These results indicate that mGluR1 activation is necessary not only for long-term depression and motor learning but also for normal neurotransmission of Purkinje cells needed for cerebellar coordination. In addition, the mGluR1 autoantibody caused facilitation of bradycardia reflex after fear conditioning. The mechanism
of this effect is now under investigation. In monkey, to investigate roles of mGluR1 in motor control, we injected the antibody into the globus pallidus and tried extracellular recording from single neurons in the globus pallidus. An angonist for mGluR1 caused increase of frequency of action potentials while an antagonist reduced the frequency. Interestingly, injection of the autoantibody caused increase of action potential firing resembling the effect by agonist rather than antagonist. The mechanism for this effect is now under investigation. Less
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