Changing distribution of GABA-like immunoreactivity in pigeon visual areas during the early posthatching period and effects of retinal removal on tectal GABAergic systems

The distribution of GABA-like immunoreactivity in the pigeon visual system was studied during the first 9 days after hatching using a mouse monoclonal antibody, mAb 3A12, to glutaraldehyde linked GABA (Matute & Streit, 1986). GABA-like immunoreactivity was seen in cell bodies as well as in neuropil at the level of both the retina and central visual regions at any posthatching age. However, the distribution of putative GABAergic cells and processes varied with age reaching the adult pattern at around 9 days. As a general observation, almost no cell bodies in the retina (except for some perikarya in the ganglion cell layer) were labeled at hatching but densely packed immunostained processes were present in the inner plexiform layer. During the next few days, GABA-immunoreactive amacrine and horizontal cells appeared and the adult distribution of GABA-like immunoreactivity was reached at around 9 days. In the other visual regions examined, the general trend in the variation of GABA-like immunoreactivity included: (1) a progressive decrease in the density of immunostained cell bodies and (2) an almost parallel increase in the concentration of stained neuropil. Since in pigeons the adult organization of visual pathways and the final distribution putative GABAergic systems are reached at around the same age, we suggest the possibility that incoming ganglion cell axons play a role in regulating the distribution of GABA-like immunoreactivity in Visual areas. This hypothesis is supported by the fact that the distribution of GABA-like immunoreactivity in the superficial layers of the optic tectum was altered following ablation of the contralateral retina immediately after hatchin

Visual acuity is reduced in alpha 7 nicotinic receptor knockout mice.

PURPOSE Nicotinic receptors (nAChRs) are part of a heterogeneous family of pentameric ligand-gated ion channels that are widely expressed in the visual system. The impact of α7 homomeric nAChRs on visual function was investigated using mutant mice lacking the α7 nicotinic receptor subunit. METHODS The spatial resolution limit was measured in α7 knockout (α7 KO) and age-matched control mice using three independent methods: an operant behavioral visual task (Prusky maze), cortical visual evoked potentials (VEPs), and the pattern electroretinogram (PERG) evoked by alternating gratings of different spatial frequencies and contrasts. RESULTS Visual acuity measured by means of the visual water maze task was significantly decreased in the α7 KO mice and, concordantly, there was a reduction of the cortical spatial resolution limit measured by VEPs. However, the PERG was normal in α7 KO mice, compared with control mice. The use of fluorescently tagged cholera toxin showed that projections from the retina segregate normally in α7 KO mice and, in line with this, the visual cortical responses elicited by stimulating either eye were normally balanced in both visual cortices and showed no retinotopic anomalies. CONCLUSIONS These findings indicate that the absence of the α7 nicotinic subunit reduces visual acuity. Because the cortical output has an abnormal spatial resolution but retinal output is preserved, it can be concluded that the low visual acuity was due to a deficit specifically present in the visual cortex

RAGE Inhibition in Microglia Prevents Ischemia-Dependent Synaptic Dysfunction in an Amyloid-Enriched Environment

This is the published version. Copyright 2014 Origlia et. al.Ischemia is known to increase the deleterious effect of β-amyloid (Aβ), contributing to early cognitive impairment in Alzheimer's disease. Here, we investigated whether transient ischemia may function as a trigger for Aβ-dependent synaptic impairment in the entorhinal cortex (EC), acting through specific cellular signaling. We found that synaptic depression induced by oxygen glucose deprivation (OGD) was enhanced in EC slices either in presence of synthetic oligomeric Aβ or in slices from mutant human amyloid precursor protein transgenic mice (mhAPP J20). OGD-induced synaptic depression was ameliorated by functional suppression of RAGE. In particular, overexpression of the dominant-negative form of RAGE targeted to microglia (DNMSR) protects against OGD-induced synaptic impairment in an amyloid-enriched environment, reducing the activation of stress-related kinases (p38MAPK and JNK) and the release of IL-1β. Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by Aβ and triggered by transient ischemia

Blocking the NGF-TrkA Interaction Rescues the Developmental Loss of LTP in the Rat Visual Cortex Role of the Cholinergic System

AbstractAlthough nerve growth factor (NGF) is a crucial factor in the activity-dependent development and plasticity of visual cortex, its role in synaptic efficacy changes is largely undefined. We demonstrate that the maintenance phase of long-term potentiation (LTP) is blocked by local application of exogenous NGF in rat visual cortex at an early stage of postnatal development. Long-term depression (LTD) and bidirectional plasticity are unaffected. At later postnatal ages, blockade of either endogenous NGF by immunoadhesin (TrkA-IgG) or TrkA receptors by monoclonal antibody rescues LTP. Muscarinic receptor activation/inhibition suggests that LTP dependence on NGF is mediated by the cholinergic system. These results indicate that NGF regulates synaptic strength in well-characterized cortical circuitries

Constitutive and AP20187-induced Ret activation in photoreceptors does not protect from light-induced damage.

Purpose Delivery of glial cell-derived neurotrophic factor (GDNF), either as a recombinant protein or by retinal gene transfer results in photoreceptor (PR) neuroprotection in genetic models of retinitis pigmentosa (RP). The mechanism of GDNF action and its direct targets in the retina remain unknown. The goal of the present study was to test the neuroprotective effect of GDNF from light-induced damage, a commonly used stimulus of PR degeneration, and to determine whether protection occurs directly on PRs. Methods Adeno-associated viral vectors (AAV) were developed that expressed either GDNF or a constitutively (RetMen2A) or pharmacologically activated chimeric GDNF receptor (Fv2Ret). Fv2Ret homodimerization and activation are induced by the administration of the small dimerizer drug AP20187. AAV2/2 vectors and the cytomegalovirus (CMV) promoter were used to transduce GDNF in the retina, whereas RetMen2A and Fv2Ret were transduced by AAV2/5 vectors and their expression restricted to PRs by the rhodopsin promoter. In vivo GDNF levels were measured by ELISA, RetMen2A and Fv2Ret expression and activation in vitro and/or in vivo were assessed by Western blot and immunofluorescence analyses. ERG measurements and histologic analyses were performed to assess morphologic and functional rescue, respectively. Results GDNF gene transfer resulted in sustained protein expression in the eye. In addition, the results confirmed in vivo that PR-restricted activation of Ret signaling occurred after either AAV-mediated expression of RetMen2A or AP20187-dependent Fv2Ret activation. However, this or AAV-mediated GDNF retinal gene transfer did not result in functional or morphologic PR protection from light-induced damage. Conclusions The results suggest that the apoptotic pathways responsible for light-induced PR degeneration are not inhibited by GDNF. However, GDNF signaling was shown to be regulated in time and levels in the retina by the AP20187/Fv2Ret system which is therefore available to be tested as gene-based therapeutic strategy in models of PR degeneration responsive to GDNF

Specific alterations of tyrosine hydroxylase immunopositive cells in the retina of NT-4 knock out mice

AbstractTo assess the effect of NT-4 deprivation on maturation of retinal circuitry, we investigated a mouse with targeted deletion of the gene encoding nt-4 (nt-4−/−). In particular, we studied neurons immunostained by an antibody recognizing tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine (DA) synthesis. We found that TH immunopositive processes were altered in the retina of nt-4−/−. Alteration of TH immunopositive processes in nt-4−/− mice resulted in changes of DA turnover, as assessed by high-pressure liquid chromatography measurements. These findings suggest that retinal NT-4 plays a role in the morphological maturation of dopaminergic retinal cells

Large Differences in Aging Phenotype between Strains of the Short-Lived Annual Fish Nothobranchius furzeri

BACKGROUND: A laboratory inbred strain of the annual fish Nothobranchius furzeri shows exceptionally short life expectancy and accelerated expression of age markers. In this study, we analyze new wild-derived lines of this short-lived species. METHODOLOGY/PRINCIPAL FINDINGS: We characterized captive survival and age-related traits in F1 and F2 offspring of wild-caught N. furzeri. Wild-derived N. furzeri lines showed expression of lipofuscin and neurodegeneration at age 21 weeks. Median lifespan in the laboratory varied from to 20 to 23 weeks and maximum lifespan from 25 to 32 weeks. These data demonstrate that rapid age-dependent decline and short lifespan are natural characteristics of this species. The N. furzeri distribution range overlaps with gradients in altitude and aridity. Fish from more arid habitats are expected to experience a shorter survival window in the wild. We tested whether captive lines stemming from semi-arid and sub-humid habitats differ in longevity and expression of age-related traits. We detected a clear difference in age-dependent cognitive decline and a slight difference in lifespan (16% for median, 15% for maximum lifespan) between these lines. Finally, we observed shorter lifespan and accelerated expression of age-related markers in the inbred laboratory strain compared to these wild-derived lines. CONCLUSIONS/SIGNIFICANCE: Owing to large differences in aging phenotypes in different lines, N. furzeri could represent a model system for studying the genetic control of life-history traits in natural populations

Aβ-Dependent Inhibition of LTP in Different Intracortical Circuits of the Visual Cortex: The Role of RAGE

This is the publisher's version, also available electronically from http://iospress.metapress.com/content/u12738257q258710/?issue=1&genre=article&spage=59&issn=1387-2877&volume=17Oligomeric amyloid-β (Aβ) interferes with long term potentiation (LTP) and cognitive processes, suggesting that Aβ peptides may play a role in the neuronal dysfunction which characterizes the early stages of Alzheimer's disease (AD). Multiple lines of evidence have highlighted RAGE (receptor for advanced glycation end-products) as a receptor involved in Aβ-induced neuronal and synaptic dysfunction. In the present study, we investigated the effect of oligomeric soluble Aβ_{1-42} on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20–200 nM) of Aβ_{1-42} were able to inhibit LTP in cortical layer II-III induced by either white matter (WM-Layer II/III) or the layer II/III (horizontal pathway) stimulation, whereas the inhibition of LTP was more susceptible to Aβ_{1-42}, which occurred at 20 nM of Aβ, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Aβ_{1-42} in the absence of RAGE (genetic deletion of RAGE) or blocking RAGE by RAGE antibody. These results indicate that nanomolar Aβ inhibits LTP expression in different neocortical circuits. Crucially, it is demonstrated that Aβ-induced reduction of LTP in different cortical pathways is mediated by RAGE

Microglial Receptor for Advanced Glycation End Product-Dependent Signal Pathway Drives β-Amyloid-Induced Synaptic Depression and Long-Term Depression Impairment in Entorhinal Cortex

This is the publisher's version, also available electronically from http://www.jneurosci.org/content/30/34/11414Overproduction of β-amyloid (Aβ) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on Aβ-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of Aβ in EC slices. Synaptic depression and LTD impairment induced by Aβ were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1β (interleukin-1β) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in Aβ-induced EC synaptic dysfunction