Biomedical subjects

Sherry L Ball

Publications and source records attributed to Sherry L Ball.

13 recordsLinked to original sources

PubMed2006

A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1).

Protein O-mannose beta1,2-N-acetyglucosaminyltransferase 1 (POMGnT1) is an enzyme involved in the synthesis of O-mannosyl glycans. Mutations of POMGnT1 in humans result in the muscle-eye-brain (MEB) disease. In this study, we have characterized a null mutation generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus. Expression of POMGnT1 mRNA was abolished in mutant mice. Glycosylation of alpha-dystroglycan was also reduced. POMGnT1 mutant mice were viable with multiple developmental defects in muscle, eye, and brain, similar to the phenotypes observed in human MEB disease. The present study provides the first genetic animal model to further dissect the roles of POMGnT1 in MEB disease.

Animals↗

PubMed2005

Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats.

Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.

Animals↗

PubMed2005

Neuroprotective effect of subretinal implants in the RCS rat.

PURPOSE: Retinal prosthetics have been designed to interface with the neural retina by electrically stimulating the remaining retinal circuits after photoreceptor degeneration. However, the electrical stimulation provided by the subretinal implant may also stimulate neurotrophic factors that provide neuroprotection to the retina. This study was undertaken to determine whether electrical stimulation from a subretinal photodiode-based implant has a neuroprotective effect on photoreceptors in the RCS rat, a model of photoreceptor degeneration. METHODS: Eyes of RCS rats were implanted with an active or inactive device or underwent sham surgery before photoreceptor degeneration. Outer retinal function was assessed with electroretinogram (ERG) recordings weekly until 8 weeks after surgery, at which time retinal tissue was collected and processed for morphologic assessment, including photoreceptor cell counts and retinal layer thickness. RESULTS: At 4 to 6 weeks after surgery, the ERG responses in the active-implant eyes were 30% to 70% greater in b-wave amplitude than the responses from eyes implanted with inactive devices, those undergoing sham surgery, or the nonsurgical control eyes. At 8 weeks after surgery the ERG responses from active-implant eyes were not significantly different from the control groups. However, the number of photoreceptors in eyes implanted with the active or inactive device was significantly greater in the regions over and around the implant versus sham-surgical and nonsurgical control eyes. CONCLUSIONS: These results suggest that subretinal electrical stimulation provides temporary preservation of retinal function in the RCS rat. In addition, implantation of an active or inactive device into the subretinal space causes morphologic preservation of photoreceptors in the RCS rat until 8 weeks after surgery. Further studies are needed to determine whether the correlation of neuropreservation with subretinal implantation is due to electrical stimulation and/or a mechanical presence of the implant in the subretinal space.

Animals↗

PubMed2003

Electrophysiological analysis of visual function in mutant mice.

The mouse has become a key animal model for ocular research. This situation reflects the fact that genes implicated in human retinal disorders or in mammalian retinal function may be readily manipulated in the mouse. Visual electrophysiology provides a means to examine retinal function in mutant mice, and stimulation and recording protocols have been developed that allow the activity of many classes of retinal neurons to be examined and which take into account unique features of the mouse retina. Here, we review the mouse visual electrophysiology literature, covering techniques used to record the mouse electroretinogram and visual evoked potential, and how these have been applied to characterize the functional implications of gene mutation or manipulation in the mouse retina.

Animals↗

PubMed2003

Identification of the gene and the mutation responsible for the mouse nob phenotype.

PURPOSE: The available evidence indicates that the naturally occurring mouse mutant nob (no b-wave) provides an animal model for the complete form of human X-linked congenital stationary night blindness (CSNB1). The goals of the present study were to identify the nob gene defect, to characterize the expression pattern of the involved gene, and to assess visual sensitivity in nob mice. METHODS: Positional cloning, screening of candidate genes, and sequencing were used to identify the nob gene. The expression pattern of the nyx gene was examined with Northern blot analysis and in situ hybridization. Visual sensitivity was measured with an active avoidance behavioral test. RESULTS: The nob phenotype is caused by an 85-bp deletion in the mouse nyx gene, which encodes the nyctalopin protein. Expression of nyx was most abundant in the retina and, in particular, in the inner nuclear layer. The nyctalopin protein contains 11 leucine-rich repeats and is flanked by cysteine rich regions, which identifies it as a member of the small leucine rich proteoglycan family. Behavioral testing shows that nob mice have a significant decrease in visual sensitivity. CONCLUSIONS: The nob mouse is a model for human CSNB1. This model will be useful in defining the role of nyctalopin in signal transmission between photoreceptors and retinal bipolar cells.

Amino Acid Sequence↗

PubMed2003

Assessment of retinal structure and function in Ames waltzer mice.

PURPOSE: In humans, mutations in protocadherin 15 are known to result in Usher Syndrome type 1F (USH1F). Patients with USH1F are born with profound hearing loss and have visual problems that develop in late childhood. Based on the phenotypic hearing loss and an associated mutation in protocadherin 15 (Pcdh15), the Ames waltzer mice have been presented as potential models for USH1F. To determine whether the Ames waltzer is a model for retinopathy in USH1F, retinal structure and function were assessed in all four available alleles of the mouse. METHODS: Activity of both the rod and cone pathways was evaluated by measuring electroretinograms (ERGs) in response to strobe flashes under dark- and light-adapted conditions, respectively. Retinas were processed with standard histochemical procedures, and retinal morphology was examined. The neural retina was dissected from normal pigmented mice at postnatal day (P)0, P5, P7, P20, P40, and P70, and the presence of Pcdh15 was determined by RT-PCR. RESULTS: The amplitude and implicit time of both the rod- and cone-mediated ERG a- and b-waves were comparable between Ames waltzer mutants and heterozygous littermates as old as 13 months. No evidence of retinal degeneration or disorganization was detected in mutant mice. Measures of retinal layer thicknesses were similar in mutant and wild-type control animals. Retinal expression of Pcdh15 was observed at all ages examined between P0 and P70. CONCLUSIONS: Although Pcdh15 is present in neural retina, its role remains unclear. Mutations in the Pcdh15 did not result in retinal abnormalities in the four alleles of Ames waltzer tested in this study. The explanation for the absence of retinal phenotype in the Ames mouse should be helpful in understanding USH1F and developing treatments for this disorder.

Animals↗

PubMed2002

Using mutant mice to study the role of voltage-gated calcium channels in the retina.

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 alpha1F 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 beta2 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.

Animals↗

PubMed2002

Role of the beta(2) subunit of voltage-dependent calcium channels in the retinal outer plexiform layer.

PURPOSE: Mutations in the alpha(1F) subunit of voltage-dependent calcium channels (VDCCs) have been shown to cause incomplete congenital stationary night blindness (CSNB2). The purpose of this study was to dentify which of the four beta subunits of VDCCs participates in the formation of this channel at the photoreceptor synapse and to determine how its absence affects visual processing. METHODS: Mice without each of the four known beta subunits of VDCCs were generated by gene targeting and transgenic rescue (CNS-beta(1), -beta(2)) or by gene targeting alone (beta(3)) or were obtained from a commercial provider (beta(4)). Retinal function and visual sensitivity were examined by electroretinography and an active avoidance behavioral test, respectively. The structure of the retina and expression of the alpha(1F) subunit were examined at the light microscopic level and by immunohistochemistry. RESULTS: Under dark-adapted conditions, CNS-beta(2)-null mice had a normal ERG a-wave, but did not have a normal b-wave. In addition, these mice showed decreased sensitivity to light. Both the a- and b-waves appear normal in the CNS-beta(1)-, beta(3)-, and beta(4)-null mice. Histologic analyses of all four mouse lines indicated that only the CNS-beta(2)-null mice had altered retinal morphology. Eyes of these mice had a thinner outer plexiform layer (OPL) than eyes of control animals. In addition, the labeling pattern of the alpha(1F) subunit in the OPL was altered in CNS-beta(2)-null mice. CONCLUSIONS: The normal distribution of the alpha(1F) subunit of the VDCCs in the OPL is dependent on the expression of the beta(2) subunit. The expression of both of these subunits is required for normal maintenance and/or formation of the OPL and synaptic transmission.

Animals↗

PubMedDate not supplied

Immunohistochemical analysis of the outer plexiform layer in the nob mouse shows no abnormalities.

In the nob mouse, a mutation in nyctalopin results in a loss of signal transmission from photoreceptors to depolarizing bipolar cells (DBCs). We used immunohistochemical techniques to assess the expression pattern of proteins found at either the photoreceptor terminal or bipolar cell dendrites within the outer plexiform layer. We labeled normal and nob retinas with antibodies against mGluR6, PKC, G0alpha, bassoon, PSD-95, the alpha1F subunit of voltage-gated calcium channels, trkB, and dystrophin. All labeling patterns in nob and normal retinas were comparable to those previously reported in mouse retina. Our results indicate that the absence of nyctalopin does not disrupt the expression pattern of other proteins known to be required for synaptic transmission.

Animals↗

PubMedDate not supplied

Pharmacological analysis of the rat cone electroretinogram.

The electroretinogram (ERG) of the cone system provides a useful noninvasive measure of the activity of the cone pathway. Despite a wide application of the cone ERG in the study of rodent models of human hereditary retinal disease, the cellular origins of the rat cone ERG have not been well defined. Here, we address this issue using a pharmacological approach that has been used previously to derive ERG response components. Agents that impair synaptic transmission at well-defined retinal loci were dissolved in saline and injected into the vitreous of adult Sprague-Dawley rats anesthetized with ketamine/xylazine, and cone ERGs were recorded approximately 2 h later. Analysis of the resulting waveforms indicated that the rat cone ERG includes a relatively small-amplitude component of negative polarity that is derived from the activity of cone photoreceptors, and perhaps retinal glial (Müller) cells. The cone depolarizing bipolar cell pathway contributes a positive potential of large amplitude to the rat cone ERG. In comparison, the contribution of hyperpolarizing bipolar cells is of negative polarity and of much smaller amplitude. The inner retina contributes a negative wave upon which higher frequency oscillations are superimposed. These results provide a foundation for interpreting changes in the waveform of the rat cone ERG that may be observed following genetic alteration or other experimental treatment.

Adult↗

PubMedDate not supplied

Probing inner retinal circuits in the rod pathway: a comparison of c-fos activation in mutant mice.

We have used wild-type mice and mice possessing defects in specific retinal circuits in order to more clearly define functional circuits of the inner retina. The retina of the nob mouse lacks communication between photoreceptors and depolarizing bipolar cells (DBCs). Thus, all light driven activity in the nob mouse is mediated via remaining hyperpolarizing bipolar cell (HBC) circuits. Transducin null (Tr alpha-/-) mice lack rod photoreceptor activity and thus remaining retinal circuits are solely generated via cone photoreceptor activity. Activation in inner retinal circuits in each of these mice was identified by monitoring light-induced expression of an immediate early gene, c-fos. The number of cells expressing c-fos in the inner retina was dependent upon stimulus intensity and was altered in a systematic fashion in mice with known retinal mutations. To determine whether c-fos is activated via circuits other than photoreceptors in the outer retina, we examined c-fos expression in tulp1-/- mice that lack photoreceptors in the outer retina; these mice showed virtually no c-fos activity following light exposure. Double-labeling immunohistochemical studies were carried out to more clearly define the population of c-fos expressing amacrine cells. Our results indicate that c-fos may be used to map functional circuits in the retina.

Animals↗

PubMedDate not supplied

Pharmacological studies of the mouse cone electroretinogram.

Electroretinography provides a useful noninvasive approach to evaluate cone pathway activity. Despite wide application of the cone ERG to characterize retinal function in transgenic mice and mouse models of human hereditary retinal disease, the cellular origins of the mouse cone ERG have not been well defined. Here, we address this issue using a pharmacological approach that has been previously applied to other species. Agents that block receptor activation at well-defined retinal loci were dissolved in saline and injected into the vitreous of anesthetized adult BALBc/By J mice; cone ERGs were recorded 1-2 h later. Analysis of the resulting waveforms indicated that the mouse cone ERG includes a cornea-negative component that is derived from the activity of cone photoreceptors and retinal glial (Müller) cells. Similar to other species, activity of cone depolarizing bipolar cells contributes a large amplitude cornea-positive potential to the mouse cone ERG. In contrast to primate but similar to rat, the mouse cone ERG includes only a small contribution from hyperpolarizing bipolar cell activity. The inner retina appears to contribute to both the a- and b-waves of the mouse cone ERG. These results provide a foundation for interpreting changes in the waveform of the mouse cone ERG that may be observed following genetic alteration or other experimental treatment.

Aminobutyrates↗

PubMedDate not supplied

Subretinal implantation of semiconductor-based photodiodes: durability of novel implant designs.

Selective degeneration of the retinal photoreceptor layers underlies blindness in retinitis pigmentosa (RP) and other inherited retinal disorders. Because there are no therapies for these patients, we are evaluating the possibility that electrical stimulation delivered to the subretinal space by a microphotodiode array (MPA) could replace, in some aspect, the function of diseased photoreceptors. Early MPA prototypes utilized gold as the electrode material, which gradually dissolved during the postoperative period following subretinal implantation. Here we present the results obtained when different MPA materials were used. Semiconductor-based silicon MPAs (2 mm in diameter; 50 microm in thickness), incorporating iridium/iridium oxide (IrOx) or platinum (Pt) electrodes, were implanted into the subretinal space of the right eye of normal cats with the use of vitreoretinal surgical techniques. Indirect ophthalmoscopy, fundus photography, ganzfeld electroretinography, and histology were used for the evaluation of the implanted retinas postoperatively. Infrared (IR) stimulation was used to isolate electrical responses generated by the MPA. The unimplanted left eyes were used for control purposes. After the implantation surgery, subretinal MPAs retained a stable position in the subretinal space. Up to 12 months after surgery, there was little change in the magnitude of the electrical response of IrOx- and Pt-based MPAs to a standard IR light stimulus. Overlying the implant, there was a near-complete loss of the outer retinal layer, which is likely to reflect obstruction of choroidal nourishment to these layers by the solid disk implant. In addition, the inner retinal layers showed variable disorganization. Away from the implant, the retina displayed a normal appearance. In comparison to electroretinograms (ERGs) obtained from unimplanted eyes, responses recorded from implanted eyes had a normal waveform but were slightly smaller in amplitude. These results indicate that IrOx and Pt improve implant electrode durability and that implants incorporating these materials into the electrode layer do not induce panretinal abnormalities.

Animals↗