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S. Kaja, D. L. Goad, E. V. Gregg, M. D. Ferrari, A. M. J. M. Van den Maagdenberg, T. P. Snutch, P. Koulen; Reduced Presynaptic Signaling in Retinal Neurons of a Transgenic Mouse Model for Familial Hemiplegic Migraine. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5796.
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© ARVO (1962-2015); The Authors (2016-present)
Migraine is a severe neurovascular disorder that affects up to 12% of the general Western population. Besides the characteristic migraine headache, one third of patients experiences migraine aura, which typically manifests as visual disturbances. Gain-of-function mutations in the Cav2.1 (P/Q-type) voltage-gated Ca2+ channel cause the severe subtype of familial hemiplegic migraine type 1 (FHM1), an established model for migraine with aura. Given the tightly controlled Ca2+ homeostasis in the retina, we hypothesized that the Cav2.1 mutation may cause disturbed Ca2+ signaling in retinal neurons.
Studies were performed in FHM1 knock-in mice with the R192Q mutation in Cav2.1 Ca2+ channels. Localization and expression of voltage-gated Ca2+ channels and intracellular Ca2+ release channels was investigated using quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Changes in intracellular Ca2+ signaling including changes in release of Ca2+ from intracellular stores were measured with optical imaging techniques.
In contrast to findings in cerebellar and cortical neurons, Cav2.1-specific immunoreactivity was reduced significantly in all layers of the R192Q knock-in neural retina, most significantly in the nuclear layers and most notably in the ganglion cell layer. qPCR revealed no change in the expression of Cav channel subtypes, however, mRNA levels of all four isoforms of auxiliary α2Δ subunits were significantly reduced. Ca2+ release from intracellular stores was significantly lower in R192Q knock-in retinal neurons.
Data from the present study suggest that the FHM1 gain-of-function mutation R192Q in Cav2.1 severely disrupts Ca2+ homeostasis in retinal neurons by reducing the expression of plasma membrane voltage-gated Ca2+ channels and by suppressing intracellular Ca2+ release. This represents a novel compensatory mechanism associated with this FHM1 mutation. While it is unclear whether the ensuing abnormal Ca2+ signaling contributes to the visual disturbances occurring during migraine aura, individual components of the affected cellular signaling pathways may represent suitable therapeutic targets for ophthalmological diseases resulting from Ca2+ dyshomeostasis.
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