Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury

Author summary Retinal ganglion cells (RGCs) are the only neurons in the retina that convey visual information to the brain, doing so via the optic nerve. Major causes of optic nerve damage and subsequent RGC death are ocular trauma and optic neuropathies. At the end-stage pathology in the retina, remaining RGCs have high neuroprotective capacity, and active resilience mechanisms exist. In contrast, in this study, we demonstrate neurodegenerative mechanisms based on the early susceptibility of peripheral ventrotemporal (VT) RGCs to degeneration after optic nerve injury. We identified the serotonin transporter (SERT) as the factor mediating VT RGC vulnerability and axon regeneration. Loss of SERT affected activation of integrin beta 3 and gene expression in the peripheral VT retina, leading to peripheral VT RGC protection and axon regeneration. Interestingly, GPNMB, a newly identified molecule mediating neuroprotection and axon regeneration in this study, is expressed in all retinal regions. However, GPNMB expression is acutely downregulated by the presence of SERT in the peripheral VT retina, leading to regional differential vulnerability of RGCs. These findings provide new molecular mechanisms underlying selective RGC vulnerability and clues that could inform further neuroprotective and regenerative strategies. Molecular insights into the selective vulnerability of retinal ganglion cells (RGCs) in optic neuropathies and after ocular trauma can lead to the development of novel therapeutic strategies aimed at preserving RGCs. However, little is known about what molecular contexts determine RGC susceptibility. In this study, we show the molecular mechanisms underlying the regional differential vulnerability of RGCs after optic nerve injury. We identified RGCs in the mouse peripheral ventrotemporal (VT) retina as the earliest population of RGCs susceptible to optic nerve injury. Mechanistically, the serotonin transporter (SERT) is upregulated on VT axons after injury. Utilizing SERT-deficient mice, loss of SERT attenuated VT RGC death and led to robust retinal axon regeneration. Integrin beta 3, a factor mediating SERT-induced functions in other systems, is also upregulated in RGCs and axons after injury, and loss of integrin beta 3 led to VT RGC protection and axon regeneration. Finally, RNA sequencing analyses revealed that loss of SERT significantly altered molecular signatures in the VT retina after optic nerve injury, including expression of the transmembrane protein, Gpnmb. GPNMB is rapidly downregulated in wild-type, but not SERT- or integrin beta 3-deficient VT RGCs after injury, and maintaining expression of GPNMB in RGCs via AAV2 viruses even after injury promoted VT RGC survival and axon regeneration. Taken together, our findings demonstrate that the SERT-integrin beta 3-GPNMB molecular axis mediates selective RGC vulnerability and axon regeneration after optic nerve injury.

Automated summary

The study demonstrates the neurodegenerative mechanisms based on the early susceptibility of peripheral ventrotemporal (VT) retinal ganglion cells (RGCs) after optic nerve injury, with serotonin transporter (SERT) identified as a key factor mediating VT RGC vulnerability. Loss of SERT affects VT RGC protection and axon regeneration, with GPNMB playing a role in the differential vulnerability of RGCs in different retinal regions. These findings provide insights into selective RGC vulnerability and potential neuroprotective strategies.