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Review
. 2016 Aug 15;594(16):4653-60.
doi: 10.1113/JP271897. Epub 2016 Jun 12.

Cellular and circuit mechanisms underlying spinocerebellar ataxias

Pratap Meera  1 , Stefan M Pulst  2 , Thomas S Otis  1   3
Affiliations
Review

Cellular and circuit mechanisms underlying spinocerebellar ataxias

Pratap Meera et al. J Physiol. .

Abstract

Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease.

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Figures

Figure 1
Figure 1. Simplified schematic diagram of the cerebellar circuit
Black arrowheads represent excitatory and red circles denote inhibitory connections. The dashed arrow indicates an unconventional connection between climbing fibres and interneurons (Szapiro & Barbour, 2007; Mathews et al. 2012). The red and blue starbursts indicate hypothesized sites of climbing fibre‐instructed, associative forms of synaptic plasticity required for associative motor learning (LTD of Purkinje fibre inputs and LTP of mossy fibre inputs, respectively). These forms of plasticity may be saturated during the SCA disease process.
Figure 2
Figure 2. Schematic diagram of the mGluR–Ca2+ hypothesis
Glutamate release from PFs activates both AMPARs and mGluR1 GPCRs. As indicated by the black arrows, mGluR1 is coupled to PLCβ, which leads to release of Ca2+ from IP3Rs on the endoplasmic reticulum. Ca2+ exerts positive feedback on mGluR1 transduction at a step early in the cascade (1) as well as at the IP3R (2). Thus, elevations in Ca2+ will exacerbate the IP3R hyperactivity observed in SCA2. Modified from Hartmann et al. (2011). DAG, diacylglycerol.
See this image and copyright information in PMC

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References

    1. Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA & Tonegawa S (1994). Deficient cerebellar long‐term depression and impaired motor learning in mGluR1 mutant mice. Cell 79, 377–388. - PubMed
    1. Airaksinen MS, Eilers J, Garaschuk O, Thoenen H, Konnerth A & Meyer M (1997). Ataxia and altered dendritic calcium signalling in mice carrying a targeted null mutation of the calbindin D28k gene. Proc Natl Acad Sci USA 94, 1488–1493. - PMC - PubMed
    1. Armbrust KR, Wang X, Hathorn TJ, Cramer SW, Chen G, Zu T, Kangas T, Zink AN, Oz G, Ebner TJ & Ranum LP (2014). Mutant β‐III spectrin causes mGluR1α mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5. J Neurosci 34, 9891–9904. - PMC - PubMed
    1. Batchelor AM & Garthwaite J (1997). Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway. Nature 385, 74–77. - PubMed
    1. Becker EB, Oliver PL, Glitsch MD, Banks GT, Achilli F, Hardy A, Nolan PM, Fisher EM & Davies KE (2009). A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. Proc Natl Acad Sci USA 106, 6706–6711. - PMC - PubMed

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