Insulin Restores Retinal Ganglion Cell Connectivity and Promotes Vision Recovery in Glaucoma
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Insulin Restores Retinal Ganglion Cell Connectivity and Promotes Vision Recovery in Glaucoma
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Insulin Restores Retinal Ganglion Cell Connectivity and Promotes Vision Recovery in Glaucoma
In neurodegenerative diseases, synaptic and dendritic changes can disrupt neural circuits, ultimately leading to neuron death. Stimulating dendrite and synapse regeneration may restore the function of damaged neural circuits. However, neurons in the central nervous system (CNS) have limited regenerative capacity, especially when injured or diseased. Therefore, identifying factors and signaling pathways that promote dendrite regeneration, re-establish functional synaptic connections, and enhance neuronal resilience is critical.
Insulin, a peptide hormone that can cross the blood-brain barrier, plays an essential role in energy balance, dendritic plasticity, and neurotransmission in the nervous system. It promotes neurite growth by supporting microtubule formation. Research has shown that insulin deficiency and resistance are linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. While intranasal insulin improves memory and mood in these patients, it remains unclear whether insulin can promote dendrite and synapse regeneration to restore neural circuit function, as well as the mechanisms involved.
Recently, Adriana Di Polo and colleagues published a study titled “Insulin restores retinal ganglion cell functional connectivity and promotes visual recovery in glaucoma” in Science Advances.
This research demonstrates that insulin can activate the mTOR pathway, promoting dendritic and synaptic regeneration in retinal ganglion cells (RGCs), thus restoring their function and improving visual behavior.
To investigate whether insulin can promote dendrite regeneration, the researchers induced ocular hypertension (OHT) in mice by injecting magnetic beads into their eyes and then treated them with insulin. The study found that OHT significantly reduced RGC dendrites, and lowering intraocular pressure alone did not promote dendrite regeneration. However, insulin treatment successfully stimulated dendrite regeneration, restoring dendritic length, coverage, and branching. Additionally, locally applied insulin penetrated the cornea and reached the retina, suggesting that insulin contributes to dendrite regeneration under OHT conditions.
Further experiments revealed that excitatory synapses between RGCs and bipolar cells were significantly reduced under OHT. Insulin treatment restored the expression of critical synaptic proteins (PSD95 and VGLUT1). Using viral vectors tagged with red fluorescent protein, the researchers visualized and quantified synapse complexes on regenerating dendrites. They found that insulin significantly restored excitatory synapse density on both proximal and distal RGC dendrites, regardless of RGC subtype or distance from the cell body.
mTORC1 and mTORC2 are key regulators, with mTORC1 primarily responsible for mRNA translation and protein synthesis, while mTORC2 regulates cytoskeletal organization and cell growth. The researchers used targeted siRNA to inhibit S6K and 4EBP1, downstream effectors of mTORC1, to explore their roles in insulin-induced dendrite regeneration. Knockdown of S6K completely blocked insulin-induced dendrite regeneration, resulting in shortened dendrites and reduced branching, while 4EBP1 knockdown had no effect. The role of S6K in regeneration was further validated in different optic nerve injury models, indicating that S6K is a critical regulator of insulin-dependent RGC dendrite regeneration.
Moreover, the study found that S6K influences mTORC2 activity by phosphorylating its key component, SIN1, which is essential for insulin-induced dendrite regeneration. Specifically, S6K phosphorylates SIN1 at Thr86 and Thr398, promoting mTORC2 activation. Knockdown of SIN1 significantly inhibited insulin-induced dendrite regeneration, highlighting its crucial role. SIN1 phosphorylation also correlates with Akt activation, which further activates mTORC1, creating a positive feedback loop that enhances protein translation and dendrite regeneration. This suggests that mTORC1 and mTORC2 interact through SIN1 to jointly promote insulin-induced dendrite regeneration in RGCs.
The researchers examined the effect of insulin on RGC survival in the OHT model. They found that insulin treatment significantly increased RGC survival, maintaining their density close to that of uninjured controls, whereas saline-treated retinas showed substantial neuronal death. Additionally, single-cell calcium (Ca²⁺) signaling analysis showed that insulin restored light-evoked Ca²⁺ transients in RGCs, with shorter decay times similar to uninjured controls. Functional tests demonstrated that insulin treatment significantly improved vision, reversing OHT-induced visual deficits.
In conclusion, this study demonstrates that insulin therapy is an effective regenerative strategy, capable of promoting dendrite and synapse regeneration in RGCs and restoring neural circuit function. These findings offer new insights into the potential application of insulin in treating glaucoma and other optic neuropathies.
Insulin Restores Retinal Ganglion Cell Connectivity and Promotes Vision Recovery in Glaucoma
Reference:
El Hajji S, Shiga Y, Belforte N, et al. Insulin restores retinal ganglion cell functional connectivity and promotes visual recovery in glaucoma. *Sci Adv*. 2024;10(32):eadl5722. doi:10.1126/sciadv.adl5722.
(source:internet, reference only)
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