Dual impairment of GABA_A- and GABA_B-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase

Abstract 

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_BRs). 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_AR)-mediated inhibitory synaptic transmissions, and attenuation of GABA_B receptor-mediated inhibition of excitatory transmissions.

Keywords:  Glutamic acid decarboxylase, Anti-GAD autoantibody, GABA, GABA_A receptor, GABA_B receptor, Purkinje cell, Cerebellum, Cerebellar ataxia