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Using Mutant Mice to Study the Role of Voltage-Gated Calcium Channels in the Retina

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Neuronal voltage-gated calcium channels (VGCCs) are critical to numerous cellular functions including synaptogenesis and neurotransmitter release. Mutations in individual subunits of VGCCs are known to result in a wide array of neurological disorders including episodic ataxia, epilepsy, and migraines. The characterization of these disorders has focused on channel function within the brain. However, a defect in the retina-specific α1F subunit of an L-type VGCC results is a loss of visual sensitivity or the incomplete form of X-linked congenital stationary night blindness (CSNB2). Based on the electroretinographic phenotype of these patients this channel type is localized to the axon terminal of photoreceptor cells and results in a loss of signal transmission from photoreceptors to bipolar cells. A mouse with a deletion of the β2 subunit of VGCCs in the central nervous system was recently shown to have a similar phenotype as CSNB2 patients. The identification of the role of VGCCs in this disorder highlights the potential association of other VGCC mutations with retinal disorders. The study of the role of these channels in normal retinal function may also be elucidated by the characterization of retinal structure and visual function in the numerous knockout, transgenic, and naturally occurring mouse mutants currently available.

Introduction

The characterization of animals with ion channel mutations provides useful information regarding their role in vivo and provides systems in which to study the pathogenesis of channelopathies.1 In fact, an extensive literature has developed where animal models have provided information regarding how abnormalities in a specific channel type including water channels, receptors, and ion channels such as K, Na, Cl and Ca2+ alter the function of systems.

A wide variety of neurological disorders have now been linked to voltage-gated calcium channel (VGCC) subunit defects.2,3,4,5,6,7,8,9 All VGCCs are composed of an α1poreforming subunit, a β and α2/δ, and possibly γ-subunits. Figure 1illustrates the topological organization of these subunits. Each VGCC type is defined according to its pharmacological sensitivities, kinetics and specific α1 subunit. To date, ten α1 (AS), four β (14), three α2/δ and eight γ-subunits have been identified.10,1,12 Additionally, for many subunits there are multiple splice variants, which create the potential for considerable functional diversity.

Figure 1. Topological organization of the three core subunits comprising a voltage-gated calcium channel.

Figure 1

Topological organization of the three core subunits comprising a voltage-gated calcium channel. The pore-forming transmembrane α1 subunit is composed of 4 homologous domains each containing 6 transmembrane segments (not shown). The α1 (more...)

Neuronal Ca2+ Channels

In the central nervous system, VGCCs are required for neurotransmitter release and they are present at two general synapse types, those exhibiting fast synaptic transmission and those that release neurotransmitter in a tonic manner. Fast synapses contain primarily the P/Q and N type channels in various ratios, which are composed of the α1A and the α1β subunit, respectively. Ribbon synapses present in the cochlea and retina release neurotransmitter tonically. They contain L-type VGCCs, which are composed of α1D, α1F, and possibly α1C subunits. In addition to synaptic transmission, as regulators of both membrane potential and intracellular Ca2+ levels, VGCCs serve diverse cellular functions such as neurite outgrowth and synaptogenesis.13,14 Thus, they are located on the cell soma as well as neuronal processes.15

VGCCs in the Retina

The retina contains two synaptic or plexiform layers. The outer plexiform layer (OPL) contains two types of synapses that connect photoreceptors to bipolar and horizontal cells. Rod photoreceptors have a ribbon synapse that is characterized by a large electron dense structure extending from the synaptic contact into the rod terminal, and four invaginating postsynaptic processes, two each from bipolar and horizontal cells.16 This “ribbon” is thought to be involved in the tonic release of neurotransmitter that occurs in the dark at this synapse.17,18 The cones also have ribbon synapses, however, each cone terminal has multiple sets of invaginating processes each from bipolar and horizontal cells. In addition, cone terminals also have conventional synapses with horizontal cells. The inner plexiform layer (IPL) contains synapses involving bipolar, amacrine and ganglion cells. Bipolar cells have ribbon synapses, although structurally they are much smaller than the ribbons found in photoreceptor terminals.

The types of VGCCs have not been studied extensively in all retinal cell types. The best studied are the slowly inactivating L-type channels that control the tonic release of neurotransmitter creating a graded potential at the axon terminal in both photoreceptors and bipolar cells.13,19,20 Although the role of P/Q- and N-type channels in the retina is unclear, it is possible that these channel types are utilized at conventional synapses present in both the OPL and IPL. In addition to synaptic localization, VGCCs such as T-type are located on the cell bodies of neurons.21

Distribution of α1 and β Subunits in the Retina

While the evidence that L-type VGCCs are localized to the presynaptic terminal of photoreceptors and bipolar cells are involved in synaptic transmission is solid, the composition of these channels is under intense scrutiny. Both the α1C and the α1D subunit and more recently, the α1F subunit of L-type VGCCs have been localized to the presynaptic terminal of photoreceptors.13,22,23,24,25 One explanation may be that multiple types of VGCCs are present at synaptic sites in the retina. A differential distribution of the L-type channel subunit α1D, between photoreceptors was noted in the cone-dominant tree shrew retina. The rod photoreceptors as well as the blue cones lacked the α1D subunit.22 In rat, differential label between the α1F and the pan α1 antibody suggests that there are different types of L-type VGCCs within the OPL and IPL, which may correspond to rod and cone photoreceptors.25 In addition to synaptic sites, some α1F label was noted within the photoreceptor inner segments and faint label in cell bodies of both inner and outer nuclear layers. Staining in the OPL, IPL, and Müller cells has also been noted using the α1C antibody.13 In addition, there exists a great deal of evidence suggesting the presence of other channel types throughout the retina although their pattern of expression remains undetermined.

The distribution of β subunit is even less clear. Western blot analysis shows that all four β subunits are expressed in the retina (Fig. 2).26 Indirect evidence showing the loss of the β2 subunit to be associated with changes in OPL structure27 and function26 strongly suggests the presence of this subunit at the photoreceptor terminal.

Figure 2. Western blots showing β subunit expression in the retina of control and the four β subunit knockout mouse lines.

Figure 2

Western blots showing β subunit expression in the retina of control and the four β subunit knockout mouse lines. All four β subunit s are expressed in the retina and the expected subunit is absent from each of the mutant mouse (more...)

Assessment of Retinal Function in Mutant Mice

When light is presented to an otherwise steady state retina the resulting changes in ionic current or evoked potential can be measured from the surface of the cornea. This response, the electroretinogram (ERG), represents the temporally summed activity of retinal cells in response to a light stimulus and is composed of two main waveforms. The most prominent waveform, the b-wave, is generated by the activation of bipolar cells.28 Under some conditions, the b-wave is preceded by a negative wave representing the hyperpolarization of photoreceptors referred to as the a-wave.29 The ERG is useful as a means to study synaptic transmission between photoreceptors and bipolar cells and thus Ca2+ channel function at the photoreceptor axon terminal. This method has been well characterized in rodents and is often used in animal studies as it is noninvasive and can be readily compared to data from human studies.

Impact of VGCC Subunit Mutations on Retinal Function

For many of the VGCC α1 and auxiliary subunits either natural mutations have been identified, or gene targeting has been used to produce null alleles (Table 1). Mutations in the α1A subunit genes of P/Q-type VGCCs have been identified in lines of mutant mice, such as rocker,30 tottering, 31 and leaner, 32 which display neurological symptoms similar to those of human patients with transient motor abnormalities.33,34 Based on labeling with specific radioligands and an analysis of mRNA, N- and P/Q-type channels utilizing the α1B and α1A subunit were reported to be present in the retina.35,36 However, little is known regarding their molecular structure and function and, until now, no information was available regarding visual function in these mice. Additionally, within the past year neurological deficits have been described in 3 knockout mice, in which the pore-forming α1G37, α1E38 and α1D39 subunit corresponding to T-type, R-type and L-type channels, respectively, were targeted. Again, although similar channel types have been shown to be present in the retina making it likely that the mutant mice will also posses retinal dysfunction, visual function has not been assessed.

Of the various animals with mutations in α1 subunits, only mutations in the human α1F have been associated with a retinal disease phenotype. A recent study examining retinal function in mice with mutations in the β subunit of VGCCs provides the first mouse model for a retinal disorder linked to a Ca2+ channel mutation. In this study, mice lacking all four β subunits were examined using electroretinography, only the CNS-β2 null mouse showed a detectable phenotype.26 There are no reports describing visual system structure or function in mice with mutations in the other auxiliary α2/δ and γ subunits. Mutations in the α1F subunit in humans and the β2 subunit in mice produce the same ERG phenotype as found in the incomplete form of X-linked congenital stationary night blindness (CSNB2), indicating that these subunits are likely to make up the major L-type channel at the photoreceptor terminals. Mutations in the β3 subunit have been shown to have an impact on organization of the lateral geniculate nucleus.40

α1F Subunit Mutations Cause CSNB2

A mouse with a mutation in the α1F subunit has not yet been reported, however, mutations in this subunit in humans cause CSNB2.5,6,41 CSNB2 is a retinal disorder resulting in decreased visual acuity and a profound loss of visual sensitivity under both scotopic and photopic conditions.42 ERG testing of these patients shows that CSNB2 is associated with a ‘negative’ ERG, where the amplitude of the b-wave is selectively reduced, indicating a loss of synaptic transmission between photoreceptors and bipolar cells.42 The loss of postreceptoral electrical activity in CSNB2 patients suggests that VGCCs composed of the α1F subunit are required for normal neurotransmitter release at the photoreceptor terminal. In support of this, the α1F subunit has been localized to the OPL and IPL of the rat retina.25 The α1F subunit has not yet been expressed in vitro and shown to be sensitive to dihyropyridines (DHP) and therefore has not been clearly classified as L-type. However, sequence analyses indicates it is likely to have the DHP binding site and the phenotype also is consistent with the absence of the photoreceptor VGCC, which is known to be an L-type channel. A second isoform of the α1F subunit also is expressed on the cell bodies of the photoreceptors. Currently the function of this isoform is unknown, although it could be involved in regulation of gene expression.

α1A Mutant Mice

In addition to L-type VGCCs the P/Q-type are dispersed throughout the brain and are especially prominent in cerebellar Purkinje and granule cells. Because this subunit is expressed in the retina we have begun to assess retinal function in the α1A mutant mice by recording light-adapted ERGs. Figure 3 shows that according to this recording method, retinal function appears to be intact. However, this preliminary analysis needs to expanded to more mice, and extended to dark-adapted conditions before final conclusions can be drawn.

Figure 3. Light-adapted electroretinograms from leaner (thin trace) and rocker (thick trace) mice.

Figure 3

Light-adapted electroretinograms from leaner (thin trace) and rocker (thick trace) mice.

β2 subunit Mutations Result in a CSNB2-Like Phenotype

Although the α1 subunit primarily determines channel characteristics, β subunits are known to play an important role in channel assembly and can modulate channel activity through interaction with the α1 subunit. The discovery that mutations in the α1F gene were responsible for CSNB2 indicates that a single α1 subunit is present as the primary L-type channels at photoreceptor terminals. This indicated that there also may be a single β subunit expressed in photoreceptors. Mutations in the β3 and β4 (lethargic) subunit genes are viable. However, mutations in the β143 and β226 subunits produced a lethal phenotype. Mice carrying the b1 mutation were rescued by expressing the subunit under the control of a skeletal muscle-specific promoter. Mice carrying the β2 mutation were rescued by expressing the subunit under the control of a cardiac muscle-specific promoter. Both the β1 and β2 rescued mice are viable and lack the expected subunit in the brain and retina. Figure 2 confirms the loss of each subunit in the retina of each respective mutant mouse.

Retinal structure and visual function were examined in each of the β subunit mutants by ERG, histology, and a behavioral task. The ERGs and the histology were normal in the β1, β3, and β4 null mice. However, CNS-specific deletion of the β2 gene had profound effects on visual function. Figure 4 shows ERGs using stimulus conditions that represent primarily rod-mediated activity.28,44 Two major ERG components found in normal mice were noted in the CNS β1, β3 and β4 null mice (Fig. 4). At all intensities, the ERG included a positive polarity b-wave and higher frequency oscillatory potentials representing the summed activity of bipolar cells and other inner retinal neurons.28,45 At higher intensities, the ERG also included a negative polarity a-wave, which is generated by the light-induced closure of cation channels along the photoreceptor outer segments46. In contrast to the results in the CNS-β1, β3 and β4 null mice, the b-wave responses of CNS-β2 null mice were reduced in amplitude at all flash intensities, although the a-wave component appeared unaffected.

Figure 4. Dark (top trace) and light (bottom trace) adapted ERGs from each b-null mouse in response to a stimulus flash of ­0.

Figure 4

Dark (top trace) and light (bottom trace) adapted ERGs from each b-null mouse in response to a stimulus flash of ­0.1 and 1.2 and log cd sec/m2 respectively.

When stimulus conditions designed to examine the cone system were used, a similar pattern was observed. Namely, the cone ERGs of CNS-β1, β3 and β4 null mice were comparable to those of normal animals (Fig. 5), while the cone ERGs of CNS-β2 null mice were markedly reduced in amplitude (Fig. 5). To determine if the two mouse cone types47 were differently affected by β subunit deletion, the function of each was examined using appropriate spectral stimuli.44 Figure 5A shows representative ERGs recorded in response to either a 400 nm or a 500 nm stimulus flash for each of the four mutant mouse lines. Distinct responses of positive polarity were obtained from CNS β1, β3 and β4 null mice, which were similar to responses obtained from wild-type animals. Under both stimulus conditions, the CNS-β2 null responses were negative in polarity and markedly reduced in amplitude (Fig. 5B).

Figure 5. A) Cone ERG waveforms recorded from each β null mouse in response to a flash of 400 nm or 500 nm light preceded by a roddesensitizing conditioning flash.

Figure 5

A) Cone ERG waveforms recorded from each β null mouse in response to a flash of 400 nm or 500 nm light preceded by a roddesensitizing conditioning flash. B) Amplitude of the cone ERGs obtained to a 400 nm or 500 nm stimulus flash. Both responses (more...)

These ERG results indicate that CNS-β2 null mice possess normal photoreceptor function, however, there is an abnormality in transmission between photoreceptors and bipolar cells in these animals. While the amplitude of the b-wave of the ERG in the CNS-β2null mice is markedly decreased there is a small-amplitude, but reproducible, b-wave-like late positive component.26 The corneal positive component was always smaller in amplitude and displayed much slower kinetics than a normal b-wave but suggests the presence of some post receptoral activity.26 A thorough ERG analysis of the CNS-β2 null mice indicates they represent a phenocopy of CSNB2.26 CSNB2 in humans was initially called incomplete CSNB because of a small amplitude b-wave with slow kinetics could be detected42while the complete form (CSNB1) resulted in a total loss of post receptoral components. The same comparison is true of the ERG in the CNS-β2 null mice versus the nob mouse, the animal model for CSNB1.48 There are at least two explanations for this remnant activity in the CNS-β2 null mouse. First, there may be a low level of expression of the α1F subunit either alone or it may partner with one of the other β subunit. Second, there may be a low level of expression of another Ca2+ channel in the photoreceptors, which is normally present at this synapse.

Immunohistochemical analysis of the retinas of the CNS-β2 null mice show they lack expression of the α1F subunit in the OPL,26 which further supports the idea that they are a model for CSNB2. In addition to an abnormal ERG, the CNS-β2 null mice show a thinning of the OPL that is associated with a loss of the ribbon synapses.27 Behavioral studies confirmed that the CNS-β2 null mice have a loss of visual sensitivity, but that under normal lighting conditions can perform a visually cued task at a normal level26 similar to CSNB2 patients.42 These data indicate that the predominant L-type channel in the photoreceptor terminals is most likely a complex between the α1F and β2 subunit and presumably an α2/δ subunit.

Conclusions and Future Directions

Current evidence suggests the α1F and the β2 subunit are paired to form the L-type VGCC at the photoreceptor axon terminal. Ca2+ channels exist in virtually all retinal cell types and presumably play diverse roles in information processing throughout the retina. Thus, defects in Ca2+ channel function can potentially lead to a variety of retinal disorders. It is likely that many human retinal eye diseases may involve Ca2+ channel mutations. By studying visual function in mice with Ca2+ channel mutations it is likely that additional animal models for retinal diseases will be identified.

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