Adenosine modulates light responses of rat retinal ganglion cell photoreceptors througha cAMP‐mediated pathway

Key points Melanopsin‐containing ganglion cell photoreceptors are post‐synaptic neurons and their light responses could therefore be modified by extracellular neuromodulators present in the mammalian retina. In this study, we show that the duration of light‐evoked spiking in these intrinsically photoreceptive retinal ganglion cells (ipRGCs) is significantly lengthened following elevation of intracellular cyclic AMP (cAMP) levels. Furthermore, we demonstrate that adenosine, a retinal neuromodulator released at night and after dark adaptation, significantly reduced light‐evoked ipRGC spiking through suppression of the cAMP‐related pathway. The effects of adenosine were mediated through activation of A 1 receptors present on ipRGCs. Adenosine‐mediated modulation of ipRGCs may represent an internal regulatory mechanism that influences a variety of light‐regulated processes such as circadian rhythm photoentrainment, pupil constriction and sleep/wakefulness.Abstract Adenosine is an established neuromodulator in the mammalian retina, with A 1 adenosine receptors being especially prevalent in the innermost ganglion cell layer. Activation of A 1 receptors causes inhibition of adenylate cyclase, decreases in intracellular cyclic AMP (cAMP) levels and inhibition of protein kinase A (PKA). In this work, our aim was to characterize the effects of adenosine on the light responses of intrinsically photosensitive retinal ganglion cells (ipRGCs) and to determine whether these photoreceptors are subject to neuromodulation through intracellular cAMP‐related signalling pathways. Using multielectrode array recordings from postnatal and adult rat retinas, we demonstrated that adenosine significantly shortened the duration of ipRGC photoresponses and reduced the number of light‐evoked spikes fired by these neurons. The effects were A 1 adenosine receptor‐mediated, and the expression of this receptor on melanopsin‐containing ipRGCs was confirmed by calcium imaging experiments on isolated cells in purified cultures. While inhibition of the cAMP/PKA pathway by adenosine shortened ipRGC light responses, stimulation of this pathway with compounds such as forskolin had the opposite effect and lengthened the duration of ipRGC spiking. Our findings reveal that the modification of ipRGC photoresponses through a cAMP/PKA pathway is a general feature of rat ganglion cell photoreceptors, and this pathway can be inhibited through activation of A 1 receptors by adenosine. As adenosine levels in the retina rise at night, adenosinergic modulation of ipRGCs may serve as an internal regulatory mechanism to limit transmission of nocturnal photic signals by ipRGCs to the brain. Targeting retinal A 1 adenosine receptors for ipRGC inhibition represents a potential therapeutic target for sleep disorders and migraine‐associated photophobia.