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.

Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine

“…Some IMCA patients have antibodies against voltage-gated Ca channel (VGCC, P/Q-type), metabotropic glutamate receptor type 1 (mGluR1), and/or glutamate receptor delta (GluR delta). Because these proteins are indispensable for LTD induction, antibodies against these proteins should cause cerebellar ataxia through blocking of LTD. Immunotherapies improved symptoms in IMCA patients having antibodies against these proteins, suggesting that recovery of LTD at PF–PC synapses would be important for the maintenance or acquisition of the internal model of movement [ 73 , 74 ]. New synapse formation.…”

LTDpathies: a Novel Clinical Concept

“…Apart from the historical controversy, ataxic symptoms in some patients with immune-mediated cerebellar ataxias (IMCAs) have been attributed to dysregulated PF-PC LTD [ 13 ]. Here, we present the novel clinical concept of “LTDpathies,” a novel group of disorders targeting LTD.…”

“…In IMCAs, various synaptic proteins, such as glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta), are targets of auto-immunity [ 14 – 16 ]. Although the auto-immunity and clinical profiles vary enormously among CAs associated with anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies (Abs), these three subtypes show the common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome [ 13 , 17 ], suggesting functional cerebellar disorders without or with weak neuronal death. Notably, anti-VGCC, anti-mGluR1, and anti-GluR delta Abs are preferentially found in IMCAs and not in other autoimmune neurological conditions such as autoimmune limbic encephalitis [ 17 ].…”

“…These studies suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism, the deregulated PF-PC LTD. We propose that these three subtypes can be included into the novel entity of “LTDpathies,” which describes PF-PC LTD-related elementary dysfunction [ 13 ].…”

“…The concept of “LTDpathies” can have practical benefits to the management of CA patients. CA associated with anti-VGCC, anti-mGluR1, and anti-GluR delta Abs commonly responds well to immunotherapies, an outstanding feature in IMCAs [ 13 , 17 ]. Thus, the new concept provides a warning for careful differential diagnosis in order to avoid the loss of therapeutic opportunities.…”