The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

Hiroshi Mitoma; Kazuhiko Yamaguchi; Jerome Honnorat; Mario Manto

doi:10.3390/brainsci12030303

The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

Brain Sci. 2022 Feb 24;12(3):303. doi: 10.3390/brainsci12030303.

Authors

Hiroshi Mitoma¹, Kazuhiko Yamaguchi², Jerome Honnorat^{3

4}, Mario Manto^{5

6}

Affiliations

¹ Department of Medical Education, Tokyo Medical University, Tokyo 160-0023, Japan.
² Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8511, Japan.
³ French Reference Center on Paraneoplastic Neurological Syndromes, Hospices Civils de Lyon, Hôpital Neurologique, 69677 Bron, France.
⁴ Institut MeLis INSERM U1314/CNRS UMR 5284, Université de Lyon, Université Claude Bernard Lyon 1, 69372 Lyon, France.
⁵ Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000 Charleroi, Belgium.
⁶ Service des Neurosciences, University of Mons, 7000 Mons, Belgium.

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.

Keywords: anti-GluR delta antibody; anti-VGCC antibody; anti-mGluR antibody; cerebellar ataxias; immune-mediated cerebellar ataxias; long-term depression; prodromal phase; spinocerebellar ataxia.