Cerebellar long-term depression and auto-immune target of auto-antibodies: the concept of LTDpathies

Abstract

There is general agreement that auto-antibodies against ion channels and synaptic machinery proteins can induce limbic encephalitis. In immune-mediated cerebellar ataxias (IMCAs), various synaptic proteins, such as GAD65, voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) are auto-immune targets. Among them, the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies remain unclear. Despite divergent auto-immune and clinical profiles, these subtypes show common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome. The favorable prognosis reflects functional cerebellar disorders without neuronal death. Interestingly, these autoantigens are all involved in molecular cascades for induction of long-term depression (LTD) of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a crucial mechanism of synaptic plasticity in the cerebellum. We suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF-PC LTD, which results in impairment of restoration or maintenance of the internal model and triggers cerebellar ataxias. The novel concept of LTDpathies could lead to improvements in clinical management and treatment of cerebellar patients who show these antibodies.

Keywords: Anti-GluR delta antibody; Anti-VGCC antibody; Anti-mGluR antibody; Cerebellar ataxias; Immune-mediated cerebellar ataxias; Long-term depression.

Fig. 1

Schematic diagram of the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta-associated cerebellar ataxias. The antibody-mediated mechanisms include dysfunction of basal synaptic transmissions and long-term depression (LTD), leading to impairment of the internal model. These functional disorders are followed by cell-mediated cell death, depending on the auto-immune stimulus. PC; Purkinje cell, GC; granule cell, IN; inhibitory interneurons, CF; climbing fiber, PF; parallel fiber, MF; mossy fiber

Fig. 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⁺]_i). On the other hand, the parallel fiber input activates metabotropic glutamate receptor-PLCβ-IP₃ signaling pathways, resulting in an increase in [Ca²⁺]_i. The conjunctive activation of these two pathways increases [Ca²⁺]_i more than the additive level. The high [Ca²⁺]_i 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 fibers, PF; parallel fibers, 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, δ; GluR delta 2, PTPMEG; megakaryocyte protein phosphatase