title: Subretinal electrical stimulation preserves inner retinal function in RCS rat retina.
abstract: OBJECTIVE
  Previously, studies showed that subretinal electrical stimulation (SES) from a microphotodiode array (MPA) preserves electroretinography (ERG) b-wave amplitude and regional retinal structure in the Royal College of Surgeons (RCS) rat and simultaneously upregulates Fgf2 expression. This preservation appears to be associated with the increased current produced when the MPA is exposed to ERG test flashes, as weekly ERG testing produces greater neuroprotection than biweekly or no testing. Using an infrared source to stimulate the MPA while avoiding potential confounding effects from exposing the RCS retina to high luminance white light, this study examined whether neuroprotective effects from SES increased with subretinal current in a dose-dependent manner.
  
  
  METHODS
  RCS rats (n=49) underwent subretinal implantation surgery at P21 with MPA devices in one randomly selected eye, and the other eye served as the control. Naïve RCS rats (n=25) were also studied. To increase SES current levels, implanted eyes were exposed to 15 min per session of flashing infrared light (IR) of defined intensity, frequency, and duty cycle. Rats were divided into four SES groups that received ERG testing only (MPA only), about 450 µA/cm2 once per week (Low 1X), about 450 µA/cm2 three times per week (Low 3X), and about 1350 µA/cm2 once per week (High 1X). One eye of the control animals was randomly chosen for IR exposure. All animals were followed for 4 weeks with weekly binocular ERGs. A subset of the eyes was used to measure retina Fgf2 expression with real-time reverse-transcription PCR.
  
  
  RESULTS
  Eyes receiving SES showed significant preservation of b-wave amplitude, a- and b-wave implicit times, oscillatory potential amplitudes, and post-receptoral parameters (Vmax and log σ) compared to untreated eyes. All SES-treated eyes had similar preservation, regardless of increased SES from IR light exposure. SES-treated eyes tended to have greater retinal Fgf2 expression than untreated eyes, but Fgf2 expression did not increase with IR light.
  
  
  CONCLUSIONS
  The larger post-receptoral responses (Vmax), greater post-receptoral sensitivity (logσ), and larger oscillatory potentials suggest SES-treated eyes maintained better inner retinal function than the opposite, untreated eyes. This suggests that in addition to preserving photoreceptors in RCS rats, SES may also promote more robust signal transmission through the retinal network compared to the control eyes. These studies suggest that the protective effects of SES on RCS retinal function cannot be improved with additional subretinal current induction from the MPA, or the charge injection provided by ERG Ganzfeld flashes was not adequately mimicked by the flashing IR light used in this study.
authors.affiliation: Rehab R&D Center, Atlanta VA Medical Center, Decatur, Georgia 30033, USA. vciavat@emory.edu
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ciavatta
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mocko
authors.forename: Moon K
authors.initials: MK
authors.lastname: Kim
authors.forename: Machelle T
authors.initials: MT
authors.lastname: Pardue
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D004596:Electroretinography; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D019736:Prostheses and Implants; D019919:Prosthesis Implantation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012160:Retina / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2