Activation of 5-HT1A Receptors Promotes Retinal Ganglion Cell Function by Inhibiting the cAMP-PKA Pathway to Modulate Presynaptic GABA Release in Chronic Glaucoma

• DOI: 10.1523/jneurosci.1685-18.2018
• Publication Date: 2018-12-12T23:24:20Z
• Authors: Xujiao Zhou; Rong Zhang; Shenghai Zhang; Jihong Wu; Xinghuai Sun
• Keywords: Male; Retinal Ganglion Cells; 8-Hydroxy-2-(di-n-propylamino)tetralin; 0303 health sciences; Pyridines; Presynaptic Terminals; Glaucoma; Isoquinolines; Cyclic AMP-Dependent Protein Kinases; Second Messenger Systems; Piperazines; Rats; 03 medical and health sciences; Bucladesine; Receptor, Serotonin, 5-HT1A; Cyclic AMP; Animals; Ocular Hypertension; Phosphorylation; Rats, Wistar; Eye Proteins; Protein Processing, Post-Translational

Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists are neuroprotective in CNS injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-hydroxy-2- (di-n-propylamino) tetralin (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 because 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 the selective GABAAreceptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic IPSCs (sIPSCs and mIPSCs, respectively) 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-protein kinase A (PKA) signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by PKA inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of phosphorylated PKA (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 RGC circuits and suppress excitotoxic processes in glaucoma.SIGNIFICANCE STATEMENTWe found that serotonin (5-HT) receptors in the retina (5-HT1A receptors) were downregulated after intraocular pressure elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic IPSCs (mIPSCs) in ON- and OFF-type retinal ganglion cells (RGCs) and RGCs in normal and glaucomatous retinal slices. Therefore, phosphorylated protein kinase A (PKA) inhibition upon release of the neurotransmitter GABA was eliminated by 8-hydroxy-2- (di-n-propylamino) tetralin (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 GABAAreceptor 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.