Time Is Cerebellum

Abstract

The cerebellum characteristically has the capacity to compensate for and restore lost functions. These compensatory/restorative properties are explained by an abundant synaptic plasticity and the convergence of multimodal central and peripheral signals. In addition, extra-cerebellar structures contribute also to the recovery after a cerebellar injury. Clinically, some patients show remarkable improvement of severe ataxic symptoms associated with trauma, stroke, metabolism, or immune-mediated cerebellar ataxia (IMCA, e.g., multiple sclerosis, paraneoplastic cerebellar degeneration, gluten ataxia, anti-GAD65 antibody-associated cerebellar ataxia). However, extension of a cerebellar lesion can impact upon the fourth ventricle or the brainstem, either by direct or indirect mechanisms, leading to serious complications. Moreover, cerebellar reserve itself is affected by advanced cell loss and, at some point of disease progression, deficits become irreversible. Such phase transition from a treatable/restorable state (the reserve is still sufficient) to an untreatable state (the reserve is severely affected) is a loss of therapeutic opportunity, highlighting the need for early treatment during the restorable stage. Based on the motto of "Time is Brain," a warning that stresses the importance of early therapeutic intervention in ischemic diseases, we propose "Time is Cerebellum" as a principle in the management of patients with cerebellar diseases, especially immune ataxias whose complexity often delay the therapeutic intervention. Indeed, this concept should not be restricted to ischemic cerebellar diseases. We argue that every effort should be made to reduce the diagnostic delay and to initiate early therapy to avoid the risk of transition from a treatable state to an irreversible condition and an associated accumulation of disability. The myriad of disorders affecting the cerebellum is a challenging factor that may contribute to irreversible disability if the window of therapeutic opportunity is missed.

Fig. 1

A schematic diagram of circuits in the cerebellar cortex. PC, Purkinje cell; GC, granule cell; IN, molecular layer interneurons; Golgi, Golgi cell; MF, mossy fiber; PF, parallel fiber; CF, climbing fiber. Two cellular mechanisms underlying cerebellar reserve are illustrated; (1) Multiple forms of synaptic plasticity and (2) convergence and divergence of mossy fiber inputs. Multiple forms of synaptic plasticity. Multiple forms of synaptic plasticity (illustrated by stars) co-exist in the cerebellar cortex [6, 7]. For example, conjunctive inputs from PF and CF on PC lead to depression of parallel fiber synapses [8]. LTD, long-term depression; LTP, long-term potentiation; RP, rebound potentiation. Excitatory neurons are shown with a white soma, whereas inhibitory neurons are shown with a black soma. Convergence of inputs from different MF in one microzone and divergence of inputs from one MF to several microzones. A group of CFs from a restricted area of the inferior olive nucleus innervates PCs which are located in a rostro-caudal sagittal area, forming a functional unit (microzone) [9]. MFs extend widely with a medio-lateral direction, terminating on GCs in different microzones [10]. For example, MF1 innervates both microzones A and B. Different MFs converge simultaneously to multiple microzones. For example, microzone A receives inputs from both MF1 and MF2. Thus, one microzone receives abundant central and peripheral inputs through MFs, which results in a redundancy of information. Most of them might be unutilized by a mechanism of silent synapse [11]. Possible mechanisms underlying cerebellar reserve. Damage to a single microzone can be compensated by other microzones reconstructing the lost internal model using synaptic plasticity and redundant central and peripheral information

Fig. 2

A schematic diagram of the decline of cerebellar function and the concept of “restorable stage” and “cerebellar reserve.” Proper therapies could restore cerebellar function in patients, whose cerebellum is at the “restorable stage,” meaning the presence of a sufficient reserve of cerebellar function. After a given threshold of neuronal loss or dysfunction in the cerebellar circuitry, cerebellar function cannot be restored anymore due to severe loss of computational capacity of the remaining cerebellar modules