Research On The Effects Of Fluoxetine On The Dematuration Of Visual Cortex And The Treatment Of Amblyopia In Adult Rats

Background and purposeAdult amblyopia is currently regarded as a "fatal disease" in ophthalmology.There is no specific treatment.The fundamental reason is that the visual cortex loses its plasticity after maturation.Our previous studies showed that fluoxetine has a "dematuration" effect on the central nervous system of adult rats and less adverse effects on other functions of the central nervous system in rats.The above studies suggest that fluoxetine is likely to be a new target for drug intervention and opens a new way for the treatment of adult amblyopia.The aim of this project is to establish an adult rat model,and analyze the mechanism of fluoxetine on the "dematuration" function of visual cortex by visual electrophysiology and molecular biology.And in order to explore the possible mechanism of fluoxetine’s dematuration of visual cortex in adult rat’s,meanwhile,we established adult rat amblyopia model,and initially explored the effect of fluoxetine combined with occlusion therapy on amblyopia in adult rats..MethodsIt was a random designed study.The rats were grouped to Cont、Flx 2W、Flx 4W、Flx 6W and Flx 8W,BFD,FLX+BFD.Pattern visual evoked potential(PVEPs)were measured in each group after 1 week of monocular deprivation(MD).The rats were grouped to control,Flx2,Flx4,BFD up on different intervention.The rats of control group were drinked conventional water for 4 weeks.The rats of Flx2 and Flx4 group were drinked 20% fluoxetine drinking water for 2 and 4 weeks.Binocular form deprivation was performed on the rats of BFD group for 2 weeks.Pattern visual evoked potential(PVEPs)were measured in each group after 1 week of covering of the nonamblyopic eye..The expression of PNNs、CSPGs、Nogo receptor、Leukocyte common antigen-related phosphatase receptor and the GABA changes of Inhibitory interneuron in the visual cortex was detected by immunohistochemistry and western blots.Rats were randomized into PW1、PW3、PW5、PW7 and PW9 group in the developmental investigation.The adult rats were randomized into Cont、FLX、BFD and Flx+BFD group.FLX group was orally used at the dosage of 0.2 mg/ml once per day for 4 weeks.The eyelids were binocularly sutured for 2 weeks to form the BFD group,and the combination of fluoxetine administration and BFD was performed in the Flx+BFD group.No any intervene was conducted in the control group.Double-immunostaining was used to observe the coexpression pattern of CSPGs staining by biotinylated wisteria floribunda lectin(WFA).The expression of Nogo receptor in the visual cortex was detected by immunohistochemistry and western blots.The changes of C/I VEP ratio、CSPGs and Nogo receptor were examined after fluoxetine and BFD.ResultsOne week of MD changed the C/I VEP ratio in the Flx 4W,Flx 6 W,Flx 8 W,BFD,FLX+BFD groups.There were a reduction of the response to stimulation of the deprived in Flx4 group while both a reduction of the response to stimulation of the deprived eye and an increased open-eye response in BFD group.There were difference in the Flx4 and FLX+BFD group but no difference in the Flx4 and BFD group.There was a increased response of the amblyopic eye and the C/I VEP ratio was changed in the rats of Flx4 and BFD group.There was statistically significant among the C/I VEP ratio of different interventions.A reduction of the response to stimulation of the nonamblyopic eye was also performed in the BFD group.In contrast,one week of covering in the control group and Flx2 group did not change binocularity in the visual cortex of the amblyopic adult rat.The expression of CSPGs and it’s receptor Nogo receptor and LAR was decreased with prolongation of fluoxetine use.The expression of CSPGs、the Nogo receptor、LAR、PV were increased during the postnatal development and reached the matural level at PW7.The expression of Nogo receptor、LAR、PVand the density of PNNs could be modulated by Fluoxetine and BFD after the critical period.There was a increased response of the amblyopic eye and the C/I VEP ratio was changed in the rats of Flx4 and BFD group.ConclusionsMore than 4 weeks of 20% fluoxetine drinking and 2 weeks BFD can restore visual cortex plasticity in the adult rat.Increase the fluoxetine drinking time cannot increase plasticity degree.Fluoxetine changes the binocularity after MD due to a reduction of the response to stimulation of the deprived eye while BFD changes it due to both a reduction of the response to stimulation of the deprived eye and an increased open-eye response.Flx and BFD can strengthen each other on the restores visual cortex plasticity in the adult rat.Chronic administration of fluoxetine promotes the recovery of visual functions in adult amblyopic rats as tested electrophysiologically and may become a new therapy of adult amblyopia.Four weeks of fluoxetine drinking can restore visual cortex plasticity in the adult rat.Increase drinking time cannot increase the effection.The expression of CSPGs、Nogo receptor and LAR were increased during the postnatal development and reached the highest level at adulthood.Chronic fluoxetine treatment and BFD cause dematuration of PNNs and the expression of Nogo receptor、LAR、PV and PNN+/PV+/the total PV+ after the critical period.Chronic administration of fluoxetine promotes the recovery of visual functions in adult amblyopic rats as tested electrophysiologically and may become a new therapy of adult amblyopia.