The pledge, the turn, and the prestige of transient cerebellar alterations in SCA6

The cerebellum controls motor behaviour. Accordingly, problems with cerebellar circuitry and function result in a number of debilitating motor diseases. The most extensively studied cerebellar disease is ataxia. The cerebellar ataxias constitute a rapidly growing list of conditions that includes autosomal dominant, autosomal recessive, X‐linked and episodic forms. Cerebellar ataxias have various cellular and molecular origins and with this heterogeneity there is also an array of pathological and behavioural manifestations. However, there are also common features in their disease pathophysiology. For example, several spinocerebellar ataxias (SCAs) exhibit similar genetic outcomes involving amino acid repeats such as polyglutamine tract expansions or they share molecular pathways that converge upon neuronal calcium regulation. From a neural systems perspective, the mechanisms of SCA can be separated into two general categories: (1) SCAs with early onset (developmental) motor dysfunction followed by neurodegeneration (e.g. SCA3; Shakkottai et al. 2011) and (2) SCAs involving late onset (adult) neurodegeneration with accompanying behavioural deficits occurring in mature individuals (SCA8; Koob et al. 1999). In this issue of The Journal of Physiology, Jayabal et al. (2017) explored the possibility of a third category. They uncovered transient developmental alterations in ataxia, with neurodegeneration and motor dysfunction starting later in life. To investigate this, the authors performed an elegant study that addressed the mechanisms of ataxia pathogenesis in a mouse model of SCA6.

SCA6 is an autosomal dominant ataxia that is caused by mutations in the CACNA1A gene. CACNA1A encodes the α1A subunit of the Ca_V2.1 P/Q‐type voltage‐gated calcium channel. In SCA6, the disease‐causing mutations induce polyglutamine (CAG) expansions that ultimately result in ataxia with unsteady gait, imbalance and stumbling, in addition to dysarthria, tremor, and eye movement defects. The onset of these symptoms is typically in the 40s, although the age of onset can range from 19 to 71 years old. Since the CACNA1A gene initiates its cerebellar expression in the first week of life in mice, Jayabal et al. (2017) examined whether Sca6^84Q/84Q mutant mice exhibit developmental alterations using slice electrophysiology, marker expression and motor behaviour paradigms. They found that in developing postnatal day (P)10–P13 mutants, Purkinje cells had surplus climbing fibre afferent contacts and they fired spike trains with elevated rates and precision. Despite these alterations, the authors did not find motor deficits during this period. What was striking was that these alterations were transient, as they were no longer observed after P21. Motor function only deteriorated much later at ∼7 months of age (Jayabal et al. 2015).

There are several possible interpretations of the results: The defects may reflect normal developmental variations that are enhanced by the mutation, the alterations are in fact impactful but their effects on behaviour are only realized by the system once the mice approach the later stages of adulthood when multiple physiological stressors arise, the defects are somewhat buried in an already chaotic developing circuit where Purkinje cell dendrites are only halfway through their morphogenesis programme, newly differentiated granule cells are at their peak of migration into the internal granular layer, inhibitory interneurons are still in the process of making their functional connections, mossy fibres still have their own transient connections directly onto Purkinje cells, and the myelination of axons is far from complete. And finally, as the authors speculate, the developing cerebellar nuclei may not yet have the functional capacity to communicate such precise circuit alterations to the rest of the motor system. In the end, these possibilities are probably not mutually exclusive. Our view is that given the transient nature of Purkinje cell firing and innervation defects in developing Sca6^84Q/84Q mice, it will be important to determine whether these abnormalities are powerful enough to predispose the motor system to fail later in life. However, because CACNA1A is widely expressed throughout the brain, it will be critical to test if Purkinje cell‐specific SCA6 mutations impact circuitry in a similar manner to the Sca6^84Q/84Q mice. In addition, it will be important to know how temporally restricting SCA6 mutations to the developing versus adult cerebellum affect in vivo circuit function and movement in the absence of any potential cumulative effects in the Sca6^84Q/84Q model. However, there are also molecular questions that arise. For instance, is the CACNA1A mutation associated with an up‐ or down‐regulation of genes involved in compensatory mechanisms that temporarily restore normal circuit function, but are inefficient or unable to persist throughout adulthood? Since it is already known that the CACNA1A gene is involved in different disorders, ranging from familial hemiplegic migraine and epilepsy to SCA6 depending on its mutation (Tottene et al. 2002), it is not unreasonable to hypothesize that each disorder may have a different transcriptional profile at different ages. We speculate that within each disease, misregulated genetic profiles leave temporal specific molecular signatures. It has been reported in SCA6, at later ages, that altered α1ACT binding to enhancer regions (e.g. BTG1 and GRN) results in decreased expression of genes normally regulated to promote Purkinje cell maturation and neurite outgrowth, although α1ACT also impacts climbing fiber innervation (Du et al. 2013). Conducting similar gene expression studies during development may prove fruitful, possibly adding insight into the mechanisms of Purkinje cell miswiring and misfiring, the lack or masking of postnatal motor deficits, or the surprising recovery of circuit function that was beautifully presented here by Jayabal et al. (2017). Lastly, it will be interesting to know if other neurological and neuropsychiatric diseases involve transient alterations, and whether the extent of developmental changes might determine disease severity.

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Competing interests

The authors have no competing interests to disclose.