Dopamine and retinal function
DA is a major neurotransmitter in the vertebrate retina, and its cellular localization and functions are similar in organisms as diverse as fish and primates (Djamgoz et al., 1997; Masson et al., 1993). In the retina, DA originates in one class of amacrine cells (ACs) and in interplexiform cells. It is transmitted via standard synaptic transmission, as well as by volume transmission, where it can diffuse up to 3mm through retinal tissue to potentially influence every type of retinal neuron, as all have receptors for DA (Yazulla and Studholme, 1995). One important function of DA in the retina is to weaken the gap junctions that couple horizontal cells (Piccolino et al., 1984; Teranishi et al., 1983). Because horizontal cells (HCs) pool the activity of photoreceptor cells across space, this DA-related uncoupling leads to significant reduction of the normally large HC receptive fields (Xin and Bloomfield, 2000), and to increased sensitivity to local (relative to contextual) stimulation (Brandies and Yehuda, 2008). A second effect of the uncoupling of HCs is reduced interaction between neurons signaling light and dark portions of space, leading to enhanced center responses (and reduced effects of surround responses) (Hedden and Dowling, 1978).
The DA receptor types found in the retina are the same as those found in the GW788388 (e.g., D1–D5), and can be roughly divided into D1 and D2 types (Brandies and Yehuda, 2008). Endogenous DA inhibits suprathreshold rod-mediated ON and OFF responses. However, with cones, DA increases excitation for ON responses, and increases inhibition for OFF responses in most cases (Popova and Kupenova, 2013). It is thought that D2 receptors are primarily involved in generating ON responses, whereas D1 receptors are mainly responsible for OFF responses (Popova and Kupenova, 2013). As a result of these asymmetries, excess DA at D2 receptors can lead to hyper-intense color perception (as seen, for example, in early schizophrenia, see below), whereas reduced DA can lead to reductions in color perception (as seen, for example, in Parkinson’s disease, see below).
Other neurotransmitters and retinal function
Glutamate is the major neurotransmitter in the vertebrate retina (de Souza et al., 2012), is the only output neurotransmitter of the photoreceptors (Copenhagen and Jahr, 1989), and is also released by bipolar and ganglion cells (Massey and Miller, 1990) (i.e., cells providing the feedforward sweep of information within and out of the retina). Moreover, glutamate output from photoreceptors is gated by the NMDA-type of glutamate receptor (Copenhagen and Jahr, 1989). This is potentially relevant to vision in schizophrenia since: 1) various lines of evidence converge in indicating that schizophrenia is characterized by NMDA dysregulation and NMDA receptor hypoactivity, leading to increased glutamate release, and this evidence forms the basis of a leading theory of the etiology of the condition (Kantrowitz and Javitt, 2010a, b; Moghaddam and Javitt, 2012; Olney and Farber, 1995); 2) NMDA dysregulation is known to cause increased DA release (Javitt, 2007), and to produce visual distortions, hallucinations, and performance on psychophysical tests of vision that resemble those found in schizophrenia (Phillips and Silverstein, 2003; Uhlhaas et al., 2007); 3) NMDA antagonists such as ketamine can cause pathological changes in the retina, including retinal hypoxia and cell death (Antal, 1979), and can cause reductions in the early (sensory) visual P1 evoked potential (Lalonde et al., 2006), which is also found in schizophrenia where it is related to level of positive symptoms (Gonzalez-Hernandez et al., 2014); and 4) many schizophrenia patients have diabetes, in many cases due to antipsychotic medication-related metabolic syndrome and weight gain, and diabetes is associated with increased retinal glutamate and retinopathy (Kowluru et al., 2001). To date, it has not been established that changes in glutamate function exist in the retina of people with schizophrenia (and therefore that any such changes contribute to visual functioning in people with schizophrenia). However, given the evidence noted here, we believe this is as fruitful an area to explore as that of retinal DA changes and vision in schizophrenia. One question that is particularly relevant is whether the glutamatergic input to, or from, two types of retinal cells in particular, midget and parasol cells, is altered. While the functional properties of these cell types continue to be topics of study, it is generally agreed that midget bipolar and ganglion cells have small receptive fields, are involved in color processing, and project into the LGN parvocellular pathway (Kolb, 1995; Kolb and Marshak, 2003). In contrast, parasol ganglion cells, which receive input from DB2 and DB3 type bipolar cells (Jacoby et al., 2000), have large receptive fields, project to the LGN magnocellular pathway, and play a role in contrast sensitivity (Crook et al., 2014). The latter has been found to be variously underactive or overactive in schizophrenia, depending on the task, and phase of illness (Butler et al., 2001; Javitt, 2009; Kelemen et al., 2013; McClure, 2001; Schechter et al., 2003), but retinal contributions to these effects have yet to be described.
Dopamine and retinal function