Activation of 5-HT1A receptors promotes retinal ganglion cell function by inhibiting the cAMP-PKA pathway to modulate presynaptic GABA release in chronic glaucoma.

Serotonin receptor agonists are neuroprotective in central nervous system (CNS) injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-OH-DPAT, a serotonin receptor (5-HT1A) agonist, in an adult male Wistar rat model of chronic glaucoma model remain unknown. We found that ocular hypertension decreased 5-HT1A receptor expression in rat retinas, as the number of retinal ganglion cells (RGCs) was significantly reduced in rats with induced ocular hypertension relative to that in control retinas, and 8-OH-DPAT enhanced the RGC viability. The protective effects of 8-OH-DPAT were blocked by intravitreal administration of the selective 5-HT1A antagonist WAY-100635 or selective GABAA receptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic inhibitory postsynaptic currents (IPSCs) of RGCs in rat retinal slices were recorded. 8-OH-DPAT significantly increased the frequency and amplitude of GABAergic sIPSCs and mIPSCs in ON- and OFF-type RGCs. Among the signaling cascades mediated by the 5-HT1A receptor, the role of cAMP-PKA signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by protein kinase A (PKA) inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of p-PKA/PKA was significantly increased in glaucomatous retinas, and 8-OH-DPAT significantly decreased p-PKA/PKA expression, which led to the inhibition of PKA phosphorylation upon relieving neurotransmitter GABA release. These results showed that the activation of 5-HT1A receptors in retinas facilitated presynaptic GABA release functions by suppressing cAMP-PKA signaling and decreasing PKA phosphorylation, which could lead to the de-excitation of RGCs circuits and suppress excitotoxic processes in glaucoma. SIGNIFICANCE STATEMENT We found that 5-HT1A receptors in the retina were downregulated after intraocular pressure (IOP) elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic inhibitory postsynaptic currents (mIPSCs) in ON- and OFF-type RGCs as well as RGCs in normal and glaucomatous retinal slices. Thus, p-PKA inhibition upon release of the neurotransmitter GABA was eliminated by 8-OH-DPAT, which led to increased levels of GABAergic mIPSCs in ON- and OFF-type RGCs, thus enhancing RGC viability and function. These protective effects were blocked by the GABAA receptor antagonist SR95531 or the 5-HT1A antagonist WAY-100635. This study identified a novel mechanism by which activation of 5-HT1A receptors protects damaged RGCs via the cAMP-PKA signaling pathway that modulates GABAergic presynaptic activity.