Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2

Abstract

Mutations in the CACNA1F gene encoding the Cav1.4 Ca2+ channel are associated with X-linked congenital stationary night blindness type 2 (CSNB2). Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated. This work provides a thorough functional characterization of the novel IT mouse line that harbors the gain-of-function mutation I745T reported in a New Zealand CSNB2 family.1 Electroretinographic recordings in IT mice permitted a direct comparison with human data. Our data supported the hypothesis that a hyperpolarizing shift in the voltage-dependence of channel activation—as seen in the IT gain-of-function mutant2—may reduce the dynamic range of photoreceptor activity. Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter. The organization of the outer plexiform layer was disrupted, and synaptic structures of photoreceptors had a variable, partly immature, appearance. The associated visual deficiency was substantiated in behavioral paradigms. The IT mouse line serves as a specific model for the functional phenotype of human CSNB2 patients with gain-of-function mutations and may help to further understand the dysfunction in CSNB.

Voltage-Gated Ca_v1 Channels in Disorders of Vision and Hearing

“…This mutation causes an unusually severe form of CSNB2, and a large (-30 mV) shift in the voltage-dependence of Ca v 1.4 activation [88]. I745T knock-in mice exhibit abnormal PR synapse morphology, reduced cone and rod transmission, and degeneration of PRs due to apoptosis [55, 59]. …”

Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina

“…Of the different classes of Ca v 1 channels (Ca v 1.1-Ca v 1.4), multiple lines of evidence indicate that Ca v 1.4 is the major Ca v 1 channel in rod and cone photoreceptors. Antibodies against Ca v 1.4 label both rod and cone terminals (11)(12)(13)(14). In mice, inactivation of CACNA1F, the gene encoding Ca v 1.4 (Ca v 1.4 KO), disrupts photoreceptor synaptic transmission and presynaptic calcium signaling (15) and prevents the maturation of photoreceptor synapses (13,16).…”

Illuminating the Multifaceted Roles of Neurotransmission in Shaping Neuronal Circuitry

“…Despite evidence of horizontal and rod bipolar neuritic sprouts being apposed to vesicle associated proteins such as VGluT1 (Regus-Leidig et al, 2014), it is not as yet known whether transmission occurs at these sites. What is certain, however, is that an optimum level of calcium influx is needed in the photoreceptor terminal to prevent sprouting because altering the calcium current without physical disruption of the channel leads to abnormal elaboration of rod bipolar cell and horizontal cell neurites (Haeseleer et al, 2004; Knoflach et al, 2013; Liu et al, 2013; Regus-Leidig et al, 2014). Perhaps of greater significance is to determine whether or not such ectopic synapses develop as a direct consequence of perturbed transmission.…”