Synaptic or Non-synaptic? Different Intercellular Interactions with Retinal Ganglion Cells in Optic Nerve Regeneration

Abstract

Axons of adult neurons in the mammalian central nervous system generally fail to regenerate by themselves, and few if any therapeutic options exist to reverse this situation. Due to a weak intrinsic potential for axon growth and the presence of strong extrinsic inhibitors, retinal ganglion cells (RGCs) cannot regenerate their axons spontaneously after optic nerve injury and eventually undergo apoptosis, resulting in permanent visual dysfunction. Regarding the extracellular environment, research to date has generally focused on glial cells and inflammatory cells, while few studies have discussed the potentially significant role of interneurons that make direct connections with RGCs as part of the complex retinal circuitry. In this study, we provide a novel angle to summarize these extracellular influences following optic nerve injury as “intercellular interactions” with RGCs and classify these interactions as synaptic and non-synaptic. By discussing current knowledge of non-synaptic (glial cells and inflammatory cells) and synaptic (mostly amacrine cells and bipolar cells) interactions, we hope to accentuate the previously neglected but significant effects of pre-synaptic interneurons and bring unique insights into future pursuit of optic nerve regeneration and visual function recovery.

Intravitreal injection of Huperzine A promotes retinal ganglion cells survival and axonal regeneration after optic nerve crush

“…The RGCs located in the retina and axons converge to form the optic nerve, and have an essential role in transmitting information from the retina to the brain (Zhang et al, 2022). Due to their unique anatomy, RGCs are susceptible to injury, including traumatic injury, ischemia/reperfusion (I/R) injury, and chronic inflammation (Fague et al, 2021).…”

Modulating amacrine cell–derived dopamine signaling promotes optic nerve regeneration and preserves visual function

“…Subsequent studies reported that ACs respond to optic nerve injury and ultimately hinder RGC axon regeneration through the presynaptic release of mobile zinc (Zn 2+ ) ( 16 – 18 ) or inhibitory neurotransmitters such as γ-aminobutyric acid and glycine ( 19 ). These findings suggest that ACs actively participate in axon regeneration after injury through various mechanisms ( 20 , 21 ).…”

“…Subsequent studies reported that ACs respond to optic nerve injury and ultimately hinder RGC axon regeneration through the presynaptic release of mobile zinc (Zn 2+ ) (16)(17)(18) or inhibitory neurotransmitters such as γaminobutyric acid and glycine (19). These findings suggest that ACs actively participate in axon regeneration after injury through various mechanisms (20,21). Dopamine (DA) is a vital neurotransmitter found throughout the CNS and plays a pivotal role in numerous physiological processes, including learning, memory, attention, and mood regulation (22,23).…”

Astroglial Cells: Emerging Therapeutic Targets in the Management of Traumatic Brain Injury

“…After an injury to neural tissue, the expression of CSPG is upregulated and greatly increased [166,167]. Studies have shown that CSPG contributes to the failure in neural tissue regeneration by inhibiting neurite growth [168][169][170]. Therefore, the release of CSPG acts as an inhibitory factor to the migration of cells and axons [171][172][173].…”