NGF Eye Administration Recovers the TrkB and Glutamate/GABA Marker Deficit in the Adult Visual Cortex Following Optic Nerve Crush

Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.

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Visual recovery following optic nerve crush in male and female wild-type and TRIF-deficient mice

Restorative Neurology and Neuroscience ◽

10.3233/rnn-201019 ◽

2020 ◽

Vol 38 (5) ◽

pp. 355-368

Author(s):

Yimeng Lina Du ◽

Elena G. Sergeeva ◽

Donald G. Stein

Keyword(s):

Optic Nerve ◽

Inflammatory Response ◽

Functional Recovery ◽

Inflammatory Responses ◽

Optic Nerve Crush ◽

Optomotor Response ◽

Nerve Crush ◽

Inflammatory Damage ◽

Visual Cortices ◽

The Brain

Background: There is growing evidence that the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway is implicated in the modulation of neuroinflammation following injuries to the brain and retina. After exposure to injury or to excitotoxic pathogens, toll-like receptors (TLR) activate the innate immune system signaling cascade and stimulate the release of inflammatory cytokines. Inhibition of the TLR4 receptor has been shown to enhance retinal ganglion cell (RGC) survival in optic nerve crush (ONC) and in ischemic injury to other parts of the brain. Objective: Based on this evidence, we tested the hypothesis that mice with the TRIF gene knocked out (TKO) will demonstrate decreased inflammatory responses and greater functional recovery after ONC. Methods: Four experimental groups –TKO ONC (12 males and 8 females), WT ONC (10 males and 8 females), TKO sham (9 males and 5 females), and WT sham (7 males and 5 females) –were used as subjects. Visual evoked potentials (VEP) were recorded in the left and right primary visual cortices and optomotor response were assessed in all mice at 14, 30, and 80 days after ONC. GFAP and Iba-1 were used as markers for astrocytes and microglial cells respectively at 7 days after ONC, along with NF-kB to measure inflammatory effects downstream of TRIF activation; RMPBS marker was used to visualize RGC survival and GAP-43 was used as a marker of regenerating optic nerve axons at 30 days after ONC. Results: We found reduced inflammatory response in the retina at 7 days post-ONC, less RGC loss and greater axonal regeneration 30 days post-ONC, and better recovery of visual function 80 days post-ONC in TKO mice compared to WT mice. Conclusions: Our study showed that the TRIF pathway is involved in post-ONC inflammatory response and gliosis and that deletion of TRIF induces better RGC survival and regeneration and better functional recovery in mice. Our results suggest the TRIF pathway as a potential therapeutic target for reducing the inflammatory damage caused by nervous system injury.

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Reduced Dendritic Spines in the Visual Cortex Contralateral to the Optic Nerve Crush Eye in Adult Mice

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.61.10.55 ◽

2020 ◽

Vol 61 (10) ◽

pp. 55 ◽

Cited By ~ 1

Author(s):

Zongyi Zhan ◽

Yali Wu ◽

Zitian Liu ◽

Yadan Quan ◽

Deling Li ◽

...

Keyword(s):

Visual Cortex ◽

Optic Nerve ◽

Dendritic Spines ◽

Optic Nerve Crush ◽

Nerve Crush ◽

Adult Mice

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Cholinergic Potentiation of Restoration of Visual Function after Optic Nerve Damage in Rats

Neural Plasticity ◽

10.1155/2017/6928489 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Mira Chamoun ◽

Elena G. Sergeeva ◽

Petra Henrich-Noack ◽

Shaobo Jia ◽

Lisa Grigartzik ◽

...

Keyword(s):

Visual Cortex ◽

Optic Nerve ◽

Evoked Potentials ◽

Visual Function ◽

Cortical Plasticity ◽

Brightness Discrimination ◽

Acetylcholinesterase Inhibitor ◽

Optic Nerve Crush ◽

Adult Rats ◽

Nerve Crush

Enhancing cortical plasticity and brain connectivity may improve residual vision following a visual impairment. Since acetylcholine plays an important role in attention and neuronal plasticity, we explored whether potentiation of the cholinergic transmission has an effect on the visual function restoration. To this end, we evaluated for 4 weeks the effect of the acetylcholinesterase inhibitor donepezil on brightness discrimination, visually evoked potentials, and visual cortex reactivity after a bilateral and partial optic nerve crush in adult rats. Donepezil administration enhanced brightness discrimination capacity after optic nerve crush compared to nontreated animals. The visually evoked activation of the primary visual cortex was not restored, as measured by evoked potentials, but the cortical neuronal activity measured by thallium autometallography was not significantly affected four weeks after the optic nerve crush. Altogether, the results suggest a role of the cholinergic system in postlesion cortical plasticity. This finding agrees with the view that restoration of visual function may involve mechanisms beyond the area of primary damage and opens a new perspective for improving visual rehabilitation in humans.

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