Dual impairment of GABAA- and GABAB-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase.
Anti-glutamate decarboxylase autoantibodies (GAD-A) are associated with a group of patients with progressive cerebellar ataxia. We reported previously that cerebellar GABA(A)-mediated synaptic transmission was presynaptically depressed by GAD-A in the cerebrospinal fluid (CSF). Using whole-cell recording of rat cerebellar slices, we found in the present study that CSF immunoglobulins from ataxic patients reduced gamma-aminobutyric acid (GABA) release from cerebellar interneurons, thereby attenuating presynaptic inhibition on neighboring excitatory synapses through GABA(B) receptors (GABA(B)Rs). Our results suggest that in in vitro slices, GAD-A elicited the pathophysiological action of reduction in GABA release, which subsequently resulted in dual synaptic impairment in the cerebellar circuit, by depression of GABA(A) receptor (GABA(A)R)-mediated inhibitory synaptic transmissions, and attenuation of GABA(B) receptor-mediated inhibition of excitatory transmissions.
Mitoma
Hiroshi
H
Mitoma Neurological Clinic, 1-2-10 Minami-Ikebukuro, Toshima, Tokyo, Japan.
Ishida
Kazuyuki
K
Shizuka-Ikeda
Masami
M
Mizusawa
Hidehiro
H
D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D002524:Cerebellar Ataxia / Q000276:immunology; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology*; D013569:Synapses / Q000187:drug effects*
D001323:Autoantibodies; D018755:GABA Agonists; D007074:Immunoglobulin G; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D005968:Glutamate Decarboxylase; D001418:Baclofen