Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias

Figure 4

Overview of the possible synaptic consequences of a decreased GABA release in the cerebellum. In normal conditions, GABA released from GABAergic neurons bind to receptors located on PC and induce an IPSC. GABA also diffuses out the synapse and binds to receptors, reducing release of the excitatory neurotransmitter glutamate. Glutamate ultimately activates NMDA receptors on excitatory neurons and is regulated in part through NO. Glutamate is taken up by astrocytes via the EAAT pathway. When GAD65Ab is produced intrathecally (), GAD65Ab may bind GAD65 and interfere with GABA release (②). Reduced GABA levels increase glutamate levels as a consequence of lower inhibition of receptors (③). Continuously high glutamate levels can develop divergent effects as detailed in the following (④). Glutamate activates microglia, which in turn releases more glutamate (④-1). Saturation or impairment of EAAT will reduce glutamate reuptake by astrocytes (④-2). Activation of xc(−) increases the extracellular glutamate release (④-3). Finally, the NMDA/NO feedback regulation fails. All these effects result in an increase in glutamate concentrations. The excessive Ca²⁺ influx stimulates calpain I and nNOS, leading to mitochondria dysfunction, ER stress, and DNA damage (④-4). In this scheme, Purkinje cells and granule cells are assumed. However, NMDA receptors are expressed in granule cells, whereas metabotropic glutamate receptors are expressed in Purkinje cells. Mossy fibers strongly excite granule cells via NMDA and AMPA receptors, contributing to cerebellar neuronal hyperactivity. GA: receptors, GB: receptors, GAD: glutamate decarboxylase, A: AMPA receptors, N: NMDA receptors, M: metabotropic glutamate receptors, EAAT: excitatory amino acid transporters, blue dots: GABA, red dots: glutamate, Glu: glutamate, Gln: glutamine, GS: glutamine synthetase, GT: glutaminase, VGlut: vesicular glutamate transporter proteins, and (—): inhibitory effects.