Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias

Abstract

In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.

Keywords: anti-GAD 65 antibody; anti-metabotropic glutamate receptor 1 antibody; anti-voltage-gated Ca channel antibody; autoantibodies; cerebellar ataxias; immune-mediated cerebellar ataxias.

Figure 1

Distribution of K⁺ channels and Ca²⁺ channels in the cerebellum. Red-colored text: K⁺ channels, blue-colored text: Ca²⁺ channels. Kv: voltage-gated K⁺ channel; BK and SK: Ca²⁺-activated K⁺ channel large-conductance (BK, Kca1.1) and small-conductance (SK, Kca2.1-3, 3.1); GIRK: G protein-coupled inwardly-rectifying K⁺ channel; P/Q, N, T; P/Q, N, and T type voltage-gated Ca²⁺ channels.

Figure 2

Schematic diagram of long-term depression (LTD) at excitatory synapses between parallel fibers and Purkinje cells. The climbing fiber input elicits complex spikes through the activation of dendritic P/Q type Ca²⁺ channels, leading to an increase in intracellular calcium concentration ([Ca²⁺]_in). On the other hand, the parallel fiber input activates metabotropic glutamate receptor-PLCβ-IP₃ signaling pathways, resulting in an increase in [Ca²⁺]_in. The conjunctive activation of these two pathways increases the [Ca²⁺]_in level more than the additive level. The high [Ca²⁺]_in level activates PKCα, and PKCα phosphorylates GluA2 of the AMPA (α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor, which results in detachment of the AMPA receptor from scaffold proteins and its internalization with PICK1 in an AP2 and clathrin-dependent manner. CF; climbing fiber, PF; parallel fiber, Glu; glutamate; AMAPA-R; AMPA receptor, mGluR1; metabotropic glutamate receptor, Cav2.1 (P/Q); P/Q type Ca²⁺ voltage-gated channel, PLC; phospholipase C, PKC; protein kinase C, IP₃; Inositol triphosphate, GRIP; Glutamate receptor interactive protein, TARP; transmembrane AMPA receptor regulatory proteins, PICK1; protein interacting with C kinase.

Figure 3

Three types of autoantigens in synapses. Autoantibodies target three types of proteins involved in synaptic transmission, leading to neurological symptoms, release machinery proteins, synaptic adhesion molecules, and receptors.