Intraocular CNTF reduces vision in normal rats in a dose-dependent manner.

PURPOSE: CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. The goal of the present study was to determine the effects of intraocular delivery of CNTF on normal rat visual function. METHODS: Full-field scotopic and photopic ERG amplitudes and spatial frequency thresholds of the optokinetic response (OKR) of adult Long-Evans rats were measured before and after intravitreous injection of CNTF or subretinal delivery of adenoassociated virus-vectored CNTF (AAV-CNTF) into one eye. Visual acuity was also measured by using the Visual Water Task in AAV-CNTF-injected animals. Multiunit luminance thresholds were recorded in the superior colliculus after CNTF injection, and the eyes were examined histologically. RESULTS: In eyes injected with a high dose of CNTF, ERG amplitudes and OKR thresholds measured through CNTF-injected eyes were decreased by 45% to 70% within 6 days after injection. ERG amplitudes had begun to recover by 21 days, whereas OKR thresholds only began to recover after 56 days. Neither OKR thresholds nor ERG amplitudes fully recovered until 90 to 100 days. When measured in the superior colliculus at 2 weeks after CNTF injection, luminance thresholds were elevated by 0.35 log units. In AAV-CNTF-injected eyes, OKR thresholds, and visual acuity were reduced by approximately 50% for at least 6 months, and scotopic and photopic ERG b-waves were reduced by 30% to 50%. Photoreceptor loss occurred in the injected regions in some of the eyes. By contrast, comparison of dose-response analysis with a dose-response study of light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses. CONCLUSIONS: Intraocular delivery of CNTF, which preserves photoreceptors in animal models of retinal degeneration, impairs visual function in normal rats at very high doses, but not at lower doses that still provide protection from constant light damage.

Afferents to Visually Responsive Grafts of Embryonic Occipital Neocortex Tissue Implanted into V1 (Oc1) Cortical Area of Adult Rats.

The aim of this study is to determine, as precisely as possible, the topography and the density of host afferents to visually responsive grafts of occipital embryonic cells implanted in block form into the occipital neocortex of adult rats. The presence of visual activity in the grafts was assessed through field potential and single unit electrophysiological recordings. Field potentials appeared triphasic in shape, had low peak-to-peak amplitude (= 100 micro V), and had normal time latencies (˜ 30 msec). Polarity reversal was never observed. Single unit recordings showed that graft neurons exhibited normal (desynchronized) spontaneous activity, had discrete receptive fields (˜ 20 masculine in dia.), and responded to small stationary light flashes. A topic projection of the visual field in the grafts was also observed. Injections of cholera toxin sabunit B (CTB) into these responsive grafts induced retrograde labeling in almost all the brain regions normally projecting to the occipital cortical areas. The visual related cortical (Oc 1, Oc2) and thalamic (LP, LD, LGB) regions of the host provide the largest contingent (70-75%) of afferents to the graft. Finally, one of the major findings of this study is that 93-97% of the labeled cortical cells were found in cortical layers V and VI with a net preference for layer VI. A noticeable proportion of these layer VI labeled neurons (15-20%) was systematically observed in sublayer VIb, very close to, or even within, the white matter. We suggest thus that grafts inserted into the occipital cortex of adult rats receive functional visual inputs through various neuronal circuits. Visual inputs could be conveyed to graft eells by: (i) regenerating axons of geniculate neurons previously innervating the injured cortical site; (ii) formation of collateral branches from thalamic axons ending normally in the host cortex close to the graft boundary; and (iii) development of neuronal processes from cells located in the host cortex, mainly in layers V and VI of the occipital areas. Depending on multiple factors, yet unknown but very likely related to the host-graft integration, the cortical circuits might be either the principal afferent inflow to the graft or only a complement to the thalamic input.