Abstract
Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.
Highlights
The last six decades have witnessed extensive discussion on the organization of synaptic plasticity in the cerebellum associated with the optimal output for learning and adaptation
Parallel fiber (PF)-Purkinje cell (PC) long-term depression (LTD) is induced by conjunctive stimulation of parallel and climbing fibers (CFs) and requires a rise in postsynaptic Ca2+ concentration [4]
Apart from these arguments, recent advances in clinical studies on immune-mediated cerebellar ataxias (IMCAs) have suggested that PF-PC LTD might be involved in various pathophysiological mechanisms
Summary
The last six decades have witnessed extensive discussion on the organization of synaptic plasticity in the cerebellum associated with the optimal output for learning and adaptation. Several other hypotheses were proposed on the role of CF inputs [8] Apart from these arguments, recent advances in clinical studies on immune-mediated cerebellar ataxias (IMCAs) have suggested that PF-PC LTD might be involved in various pathophysiological mechanisms. Cerebellar ataxia (CA) associated with antibodies (Abs) toward VGCC, mGLuR1, and GluR delta shows the common feature of good responses to immunotherapy, suggesting a common underlying functional disorder [9,10,11]. Based on these observations, we recently proposed the entity of LTDpathy to represent a pathophysiological spectrum of LTD-related functional disturbances [10,11]. The aim of this review is to integrate current physiological knowledge about LTD dysfunctions in IMCAs and SCA and to re-assess the concept of LTDpathy and its clinical significance
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