Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_24_библиотеки_им_акад_М_И_Перельмана

Mwk mice show cerebellar ataxia long before the loss of PCs occurs, suggesting that their motor decits are caused by neuronal dysfunction rather than cell death. In the cerebel­lum, TRPC3 expression starts in the second postnatal week and peaks at 3weeks postnatally (Becker etal. 2009). The increase in TRPC3 expression coincides with the critical

at disease onset revealed changes in lipid metabolism, par­ticularly abnormal sphingolipid biosynthesis (Dulneva etal.

entiation that is impaired in the Mwk cerebellum, mutant PC arborization was improved upon the addition of C6-ceramide in organotypic slice cultures (Dulneva etal. 2015).

The dendritic arborization of PCs is tightly linked to the establishment of the cerebellar circuitry. Developing PCs receive projections from two major afferent pathways, climbing bre (CF) axons from the inferior olive and paral­lel bre axons from granule cells. CFs extend along the proximal two-thirds of the dendritic arbour and form exten­sive excitatory synapses implicated in providing error sig­nals critical for cerebellar-dependent learning. In the Mwk cerebellum, the CF innervation territory is signicantly reduced alongside the observed dendritic phenotype (Dulneva etal. 2015) (Fig.69.3b). Similar impairments in CF innervation occur from a very early age in the cerebel­lum of SCA1 82Q mice exhibiting overactive mGluR1 sig­nalling (Ibrahim etal. 2017).

Functionally, TRPC3 plays a key role in glutamatergic syn­aptic transmission downstream of mGluR1. mGluR1 activa­tion results in a slow excitatory postsynaptic current (sEPSC) and inositol triphosphate receptor type 1 (IP3R1)-dependent intracellular calcium release (Fig. 69.2). Studies in Trpc3 knockout mice have demonstrated that TRPC3 is required for the sEPSC following mGluR1 activation in PCs (Hartmann et al. 2008). Similarly, TRPC3 mediates the mGluR1-dependent sEPSC in type II UBCs (Sekerková et al. 2013). The Mwk mutation alters TRPC3 gating and increases TRPC3-mediated sEPSC in PCs (Becker et al.

2009) (Fig.69.3c) and UBCs (Sekerková etal. 2013).

TRPC3 also contributes to the intrinsic ring activity of PCs. PCs generate two distinct types of action potentials; simple spikes are the result of spontaneous high-frequency repetitive ring, whereas complex spikes are low-frequency ring-driven by CF excitation. Simple spike ring displays heterogeneity, with Z- PCs ring at a higher rate than Z+ PCs (Zhou etal. 2014). Both pharmacological inhibition as well as genetic manipulation of TRPC3 revealed a critical role for TRPC3 for this functional heterogeneity (Wu etal. 2019). Consistent with the role of TRPC3 in PC simple spike ring, Sekerková etal. (2013) demonstrated enhanced PC simple spike activity in the Mwk cerebellum. This increased PC simple spike activity is restricted to Z- PCs, consistent with the greater expression of TRPC3 in these cells (Wu et al.

Evidence from several ataxic mouse models has suggested disrupted PC simple spiking activity as a common mecha­nism underlying cerebellar ataxia. In most ataxias altered PC simple spiking activity accompanies motor impairments and precedes PC degeneration and death (Cook et al. 2020). Furthermore, correction of aberrant PC simple spike activity from the early stages of the disease was shown to preserve motor coordination and limit PC degeneration (Hourez etal.

underlying multiple SCAs that could be targeted therapeu­tically. The discovery of the Mwk mutation and subse­quently of the human gain-of-function mutations in TRPC3 (Fogel etal. 2015) and mGluR1 (Watson etal. 2017) have highlighted the detrimental effects of overactive mGluR1­TRPC3 signalling on cerebellar functioning resulting in disease. Since then, accumulating evidence from human and animal models has established increased mGluR1­TRPC3 signalling as a key pathway underlying multiple cerebellar ataxias (Power etal. 2016b; Meera etal. 2017), suggesting that targeting this pathway might be a promising approach to treat a broad range of SCAs. Further research is required to better understand the differences between loss and gain of mGluR1 and TRPC3 function in patients with distinct SCAs to exploit this pathway therapeutically. Finally, overactive TRPC3 has been suggested as a poten­tial contributor to other neurological diseases including Parkinson’s disease (Sukumaran et al. 2017) and schizo­phrenia (Chen etal. 2019), suggesting that the Mwk mouse could be employed as a potential tool to unravel the role of TRPC3 in other diseases beyond cerebellar ataxia.

lar disorders, and involvement of different regions of the

clinical decits that can occur with cerebellar damage or

Vestibular eye movements or VOR acts to stabilize gaze during head rotations (rotational or rVOR) or translations (translational or tVOR). The VOR may also be affected by cerebellar lesions, including the nodulus/uvula and the oc­culus/paraocculus. A clear separation of function for the rVOR between these two general areas is not yet possible, but the occulus seems more concerned with high-frequency, rapid VOR responses and the nodulus/uvula with lower fre­quency, sustained responses (Park etal. 2013). Lesions in the occulus/paraocculus may produce changes in the ampli­tude and direction of the VOR (typically causing an inappro­priate upward component with horizontal head rotations) (Kheradmand and Zee 2011). Lesions in the nodulus/uvula produce many vestibular abnormalities (see Fig.70.2); some are related to the so-called velocity storage mechanism (VSM). The VSM, acting as an integrator, improves the inherently poor, low-frequency performance of the rVOR.The labyrinth cannot accurately transduce sustained motion because of limitations in its inherent mechanical properties. Accordingly, there is a mechanism in the vestibu­lar nuclei (VN) that integrates signals from the semicircular canals and improves the delity of the brain’s estimate of self-rotation. The nodulus controls the time constant of the VSM integrator, and nodulus lesions, by removing GABA-B related Purkinje cell inhibition to the VN, prolong the action of the VSM, leading to instability that may cause periodic alternating nystagmus (PAN). PAN is due to the combined effect of vestibular nucleus disinhibition, producing a unidi­rectional nystagmus, and an intact adaptive mechanism that attempts to null the nystagmus, causing it to change direction every few minutes. The nodulus is also important for com­bining head orientation information from the otoliths (with respect to gravity) and the semicircular canals, to help the brain distinguish tilt (from the pull of gravity) and translation (from self-motion), both of which rely on otolith activation (Angelaki and Yakusheva 2009). The nodulus/uvula also integrate linear acceleration inputs from the otoliths into velocity signals for the tVOR (Walker etal. 2010). Diffuse cerebellar lesions profoundly impair the tVOR, whereas an rVOR can still be generated though its amplitude and direc­tion may be incorrect (De Schutter etal. 2019). Prolongation of the VSM may manifest as inability to suppress post­rotatory vestibular nystagmus with tilting the head (known as ‘dumping’ or tilt suppression) (Lee etal. 2017), or as abnor­mal patterns of nystagmus after sustained head shaking or when the head is brought down in certain positions (i.e., positional nystagmus). These ndings are commonly seen with cerebellar lesions that localize to the nodulus and uvula (De Schutter etal. 2019; Kim etal. 2021; Choi etal. 2018).

during visual stimulation and also a slowly decaying after­nystagmus (OKAN) that occurs in the dark. The OKAN shares the same velocity-storage mechanism with the VOR. With occular lesions, the OKN shows reduced velocity (Zee et al. 1981) and with lesions of the nodulus/uvula, OKAN is prolonged and the direction of eye movement may not match the direction of moving visual target (Walker and Zee 1999).

2020). While gaze-evoked and rebound nystagmus are hall-

ocular function either from the tVOR or the rVOR, or verti­cal pursuit (Leigh and Zee 2015; Leigh etal. 2002).

The cerebellum also inuences vergence and control of ocular alignment. A vergence is the simultaneous movement of both eyes in opposite directions to maintain a binocular single vision with either near viewing (convergence) or dis­tance viewing (divergence). While vergence abnormalities are common in cerebellar disorders (more so as divergence insufciency than convergence insufciency), the specic anatomical localization of vergence pathways within the cer­ebellum has not been fully dened but they may involve the vermis, FOR, and interposed nucleus (Kang et al. 2018; Sander etal. 2009). Esotropia—i.e., the inward turning of the eyes—may occur in cerebellar disease, and since the esode­viation is greater at distance, it has been attributed to a diver­gence paralysis (Sander etal. 2009). Cerebellar disorders can also manifest with an alternating skew deviation, in which on eccentric horizontal gaze there is a vertical misalignment with the abducting eye usually higher. Occasionally, there is an ocular tilt reaction (OTR) in which one eye is higher than the other, the head is tilted toward the side of the lower eye and there is a counter-rolling (torsion) of the eyes such that the higher eye is intorted and the lower eye extorted. Lesions in various parts of the cerebellum have been associated with this nding (Leigh and Zee 2015).