Dopamine differentially affects retinal circuits to shape the retinal code.

Dopamine has long been reported to enhance antagonistic surrounds of retinal ganglion cells (RGCs). Yet, the retina contains many different RGC subtypes and the effects of dopamine can be subtype-specific. Using multielectrode array (MEA) recordings we investigated how dopamine shapes the receptive fields of RGCs in the mouse retina. We found that the non-selective dopamine receptor agonist apomorphine can either increase or decrease RGCs' surround strength, depending on their subtype. We then used two-photon targeted patch-clamp to target a specific RGC subtype, the transient-Off-αRGC. In line with our MEA recordings, apomorphine did not increase the antagonistic surround of transient-Off-αRGCs but enhanced their responses to Off stimuli in the centre receptive field. Both D1 - and D2 -like family receptor (D1 -R and D2 -R) blockers had the opposite effect and reduced centre-mediated responses, but differently affected transient-Off-αRGC's surround. While D2 -R blocker reduced surround antagonism, D1 -R blocker led to surround activation, revealing On responses to large stimuli. Using voltage-clamp recordings we separated excitatory inputs from Off cone bipolar cells and inhibitory inputs from the primary rod pathway. In control conditions, cone inputs displayed strong surround antagonism, while inputs from the primary rod pathway showed no surround. Yet, the surround activation in the D1 -R blockade originated from the primary rod pathway. Our findings demonstrate that dopamine differentially affects RGC subtypes via distinct pathways, suggesting that dopamine has a more complex role in shaping the retinal code than previously reported. KEY POINTS: Receptive fields of retinal ganglion cells (RGCs) have a centre-surround organisation, and previous work has shown that this organisation can be modulated by dopamine in a light-intensity-dependent manner. Dopamine is thought to enhance RGCs' antagonistic surround, but a detailed understanding of how different RGC subtypes are affected is missing. Using a multielectrode array recordings, clustering analysis and pharmacological manipulations, we found that dopamine can either enhance or weaken antagonistic surrounds, and also change response kinetics, of RGCs in a subtype-specific manner. We performed targeted patch-clamp recordings of one RGC subtype, the transient-Off-αRGC, and identified the underlying circuits by which dopamine shapes its receptive field. Our findings demonstrate that dopamine acts in a subtype-specific manner and can have complex effects, which has implications for other retinal computations that rely on receptive field structure.

Inhomogeneous Encoding of the Visual Field in the Mouse Retina.

Stimulus characteristics of the mouse's visual field differ above and below the skyline. Here, we show for the first time that retinal ganglion cells (RGCs), the output neurons of the retina, gradually change their functional properties along the ventral-dorsal axis to allow better representation of the different stimulus characteristics. We conducted two-photon targeted recordings of transient-Offα-RGCs and found that they gradually became more sustained along the ventral-dorsal axis, revealing >5-fold-longer duration responses in the dorsal retina. Using voltage-clamp recordings, pharmacology, and genetic manipulation, we demonstrated that the primary rod pathway underlies this variance. Our findings challenge the current belief that RGCs of the same subtype exhibit the same light responses, regardless of retinal location, and suggest that networks underlying RGC responses may change with retinal location to enable optimized sampling of the visual image.

Involvement of aberrant calcium signalling in herpetic neuralgia.

Alpha-herpesviruses, herpes simplex viruses (HSV) and varicella zoster virus (VZV), are pathogens of the peripheral nervous system. After primary infection, these viruses establish latency within sensory ganglia, while retaining the ability to reactivate. Reactivation of VZV results in herpes zoster, a condition characterized by skin lesions that leads to post-herpetic neuralgia. Recurrent reactivations of HSV, which cause mucocutaneous lesions, may also result in neuralgia. During reactivation of alpha-herpesviruses, satellite glial cells (SGCs), which surround neurons in sensory ganglia, become infected with the replicating virus. SGCs are known to contribute to neuropathic pain in a variety of animal pain models. Here we investigated how infection of short-term cultures of mouse trigeminal ganglia with HSV-1 affects communication between SGCs and neurons, and how this altered communication may increase neuronal excitability, thus contributing to herpetic neuralgia. Mechanical stimulation of single neurons or SGCs resulted in intercellular calcium waves, which were larger in cultures infected with HSV-1. Two differences were observed between control and HSV-1 infected cultures that could account for this augmentation. Firstly, HSV-1 infection induced cell fusion among SGCs and neurons, which would facilitate the spread of calcium signals over farther distances. Secondly, using calcium imaging and intracellular electrical recordings, we found that neurons in the HSV-1 infected cultures exhibited augmented influx of calcium upon depolarization. These virally induced changes may not only cause more neurons in the sensory ganglia to fire action potentials, but may also increase neurotransmitter release at the presynaptic terminals in the spinal cord. They are therefore likely to be contributing factors to herpetic neuralgia.

Glutamate release from satellite glial cells of the murine trigeminal ganglion.

It has been proposed that glutamate serves as a mediator between neurons and satellite glial cells (SGCs) in sensory ganglia and that SGCs release glutamate. Using a novel method, we studied glutamate release from SGCs from murine trigeminal ganglia. Sensory neurons with adhering SGCs were enzymatically isolated from wild type and transgenic mice in which vesicular exocytosis was suppressed in glial cells. Extracellular glutamate was detected by microfluorimetry. After loading the cells with a photolabile Ca(2+) chelator, the intracellular Ca(2+) concentration was raised in SGCs by a UV pulse, which resulted in glutamate release. The amount of released glutamate was decreased in cells with suppressed exocytosis and after pharmacological block of hemichannels. The data demonstrate that SGCs of the trigeminal ganglion release glutamate in a Ca(2+)-dependent manner.

Satellite glial cells in dorsal root ganglia are activated in experimental autoimmune encephalomyelitis.

Pain is a serious and common problem with patients suffering from multiple sclerosis (MS). Very little has been done to investigate the peripheral mechanisms of pain in MS. Here we used a mouse model of experimental autoimmune encephalomyelitis (EAE) to investigate the possible contribution of satellite glial cells (SGCs) to pain in MS. EAE mice had reduced pain thresholds 10 days after disease induction. We examined dorsal root ganglia and found increased expression of glial fibrillary acidic protein in SGCs, a marker of SGC activation, and increased coupling among SGCs, a known component of activated SGCs. Activated SGCs have previously been shown to contribute to pain in other classical neuropathic pain models, suggesting that pain in multiple sclerosis has a peripheral component.