You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Neuron-glia signaling in developing retina mediated by neurotransmitter spillover}
Article:
Abstract:
Neuron-glia interactions play a critical role in the maturation of neural circuits; however, little is known about the pathways that mediate their communication in the developing CNS. We investigated neuron-glia signaling in the developing retina, where we demonstrate that retinal waves reliably induce calcium transients in Müller glial cells( MCs). During cholinergic waves, MC calcium transients were blocked by muscarinic acetylcholine receptor antagonists, whereas during glutamatergic waves, MC calcium transients were inhibited by ionotropic glutamate receptor antagonists, indicating that the responsiveness of MCs changes to match the neurotransmitter used to support retinal waves. Using an optical glutamate sensor we show that the decline in MC calcium transients is caused by a reduction in the amount of glutamate reaching MCs. Together, these studies indicate that neurons and MCs exhibit correlated activity during a critical period of retinal maturation that is enabled by neurotransmitter spillover from retinal synapses.
Introduction:
There is rich research history demonstrating the important role glial cells play in developing and maintaining neural circuits( Garrido, 2013). In the mature brain, glial cells provide structural scaffolding and create physical barriers that compartmentalize synapses and limit diffusion of neurotransmitters. In addition, glial cells express a variety of neurotransmitter receptors. Activation of glial receptors causes increases in intracellular calcium that in turn may lead to the secretion of factors that influence circuit function( Haydon and Nedergaard, 2015). In the developing brain, glial cells secrete factors that are important for neuronal differentiation, migration, axonal pathfinding and synaptogenesis( Clarke and Barres, 2013; Garrido, 2013; Chung et al., 2015). However, the mechanisms that are used for neuron-glial signaling in the developing CNS remain poorly defined. There are three types of glial cells in the retina: Müller cells( MCs), astrocytes, and microglial cells. MCs, the principal glial cells of the retina, stretch radially across its thickness from the outer limiting membrane to the inner limiting membrane, sending processes throughout the inner and outer plexiform layers. MC processes envelop synapses of every neuron type, placing these cells in an ideal position to receive and respond to neuronal signals( Newman and Reichenbach, 1996; Newman, 2004, 2005; Reichenbach and Bringmann, 2013). In adult retina, MCs maintain retinal homeostasis and integrity( Byrne et al., 2013), and more recently they have been implicated in delivery of retinol to replenish cone opsin chromophore( Xue et al., 2015). In zebrafish, MC ablation does not affect the laminar organization of the inner plexiform layer( IPL, Randlett et al., 2013) or the structure or organization of synapses in the outer plexiform layer( Williams et al., 2010), in sharp contrast to ablation of MCs in developing( Dubois-Dauphin et al., 2000) and adult mice( Byrne et al., 2013; Shen et al., 2012), which leads to dramatic rearrangements retinal structure( Byrne et al., 2013). However, unlike radial glial cells in the cortex and cerebellum, the role of MCs in retinal development has not been fully explored. MCs are the last retinal cell types to mature, integrating into neuronal circuits during the first two postnatal weeks( Jadhav et al., 2009; Williams et al., 2010) when the inner retina is undergoing robust synaptogenesis. During this developmental period, the retina is spontaneously active, and ganglion cells( the output cells of the retina) exhibit depolarizations that spread laterally across the retina, a phenomenon termed retinal waves. These waves are mediated by circuits that change as the retina matures( Blankenship and Feller, 2010). From postnatal day 1( P1) to P9, retinal waves are mediated by cholinergic circuits. As bipolar cells integrate into the circuit( P10–P14), the waves become mediated by glutamatergic signaling. At eye opening( P14), light activated signaling begins and retinal waves cease. Both cholinergic( Ford et al., 2012) and glutamatergic( Blankenship and Feller, 2010; Firl et al., 2013) retinal waves are associated with volume release of neurotransmitter, where the neurotransmitter is not restricted to the synaptic cleft, but spills out into the extracellular space, allowing activation of receptors on nearby ganglion cells. Hence, these waves provide a robust source of neurotransmitter that could mediate periodic activation of MCs during retinal development. Here we investigated if MCs participate in retinal waves as they integrate into neuronal circuits. We simultaneously performed whole-cell recordings of retinal ganglion cells( RGCs) and two-photon imaging of calcium indicators or glutamate sensors expressed specifically in MCs in order to investigate if neurotransmitters released during retinal waves reliably induce calcium transients in MCs. In addition, we determined which receptors mediate these neuron-glia interactions. Our results indicate that MCs express a complement of receptors that allow detection of neurotransmitters released during retinal waves, resulting in parallel activation of this glial network prior to eye opening.
Discussion:
In this study we elucidated the spatio-temporal characteristics and molecular pathways by which neurons and MCs communicate in the developing retina. We found that retinal waves were correlated with calcium transients in a large proportion of MCs, demonstrating that spontaneous activity encompasses both neuronal and glial networks at this age. Our physiological results indicate that MCs express multiple neurotransmitter receptor types throughout this period, allowing neuronal control of MC activity to be sustained as neuronal synchronization shifts from being dependent on cholinergic to glutamatergic signaling. The proportion of MCs that responded to waves with calcium transients decreased significantly from P9 to P11, despite the presence of retinal waves. This age-dependent decline in MC activation during retinal waves was caused by an increase in glutamate transporter expression, which restricted glutamate spillover from nearby synapses limiting activation of MC AMPARs. These data indicate that MCs in the developing retina use multiple signaling pathways to participate in spontaneous, correlated activity with neurons during a crucial period of retinal development. Many different signaling mechanisms have been implicated in inducing calcium transients in astroglial cells throughout the peripheral and central nervous system( Volterra et al., 2014; Haydon and Nedergaard, 2015; Nimmerjahn and Bergles, 2015). The robustness and mechanisms of signaling vary tremendously, even at the same synapses, with age, preparation, and state of arousal. Our data indicate that MCs in the retina prior to eye opening are capable of responding to different neurotransmitters with increases in intracellular calcium( Figures 2A, 3A). Neurotransmitter-evoked calcium transients were observed in the stalks and lateral processes of MCs that transverse the IPL during a time when there is robust synaptogenesis. These multiple receptors allow MCs to detect neurotransmitter released during retinal waves whether it is ACh or glutamate, thereby extending the developmental period over which neuron-glia signaling occurs. The neuron-glia signaling we observed between neurons and MCs in the retina during glutamatergic waves is similar to signaling that occurs in Bergmann glial cells( BGs), a type of radial astroglial cell found in the cerebellum. BGs express calcium permeable AMPARs that are activated by glutamate released at parallel and climbing fiber synapses( Bergles et al., 1997; Clark and Barbour, 1997; Piet and Jahr, 2007), raising the possibility that AMPAR expression may be a conserved properties of radial-type astroglial cells. Although the role of AMPARs in BG activity is still controversial( Müller et al., 1996; Iino et al., 2001; Nimmerjahn et al., 2009), in vivo studies indicate that calcium signaling in BGs during locomotion depends on the activation of AMPARs( Nimmerjahn et al., 2009) and disruption of this signaling( Iino et al., 2001; Saab et al., 2012), results in prolonged synaptic events that are associated with altered motor behavior and motor learning. Moreover, the mechanism of interaction between neurons and MCs we observed during cholinergic retinal waves is similar to previous findings in visual cortex and hippocampus, where cholinergic neuron stimulation leads to astrocyte calcium transients via activation of muscarinic acetylcholine receptors and require IP3R2( Chen et al., 2012; Navarrete et al., 2012). Whether neuronal activity during retinal waves guides the development of MCs is still unclear. MCs exhibit dramatic morphological changes during the period from P7–P11 as their fine processes grow laterally into the IPL and ensheath synapses. Ensheathment of synapses by astrocytes has been shown to promote functional isolation of synaptic signaling by creating a barrier to diffusion of neurotransmitters and by placing neurotransmitter transporters near sites of release. It is possible that ablation of AMPARs in MCs would result in retraction of the lateral processes away from synapses, as observed in BGs after inhibition of calcium permeable AMPARs( Iino et al., 2001) or genetic ablation of GluA1 and GluA4( Saab et al., 2012). Our findings in the developing retina differ from studies performed in the adult retina, in which glutamate does not evoke calcium transients in MCs( Newman and Zahs, 1997; Newman, 2005), suggesting that glutamaterigic signaling through AMPARs in these cells may be limited to the early stages of synapse formation and refinement. Astrocytes have also been shown to play critical roles in promoting the refinement and maturation of neural circuits( Stevens, 2008; Clarke and Barres, 2013; Chung et al., 2015) by secreting synaptogenic factors, such as thrombospondin, hevin, protocadherins, BDNF, and TGF-beta, which are critical for synapse formation between RGCs and their central targets in the brain( reviewed in Chung and Barres, 2012; Clarke and Barres, 2013). In addition, astrocytes play an important role in refining nascent circuits in the visual system by engulfing unused or inappropriate synapses( Chung et al., 2015). Our findings indicate that robust signaling occurs between retinal neurons and MCs between the ages P7 and P11, a time period when there is robust synaptogenesis in the retina( Hoon et al., 2014). The close lineage relationship and functional similarities between astrocytes and MCs increase the possibility that MCs perform similar roles in the retina, particularly in regions such as the IPL where they are the sole astroglial cell. Previous studies have shown that changes in intracellular calcium can trigger the release of so-called gliotransmitters such as ATP, glutamate and D-serine from astrocytes that can influence the activity of surrounding neurons( Araque et al., 2014; Newman, 2015). In the retina, activation of AMPARs promotes the release of D-serine, a co-agonist of NMDA receptors in ganglion cells, that has been shown to play an important role in synaptic plasticity( Stevens, 2008; Sullivan and Miller, 2010), raising the possibility that MC activity induced during retinal waves participates in synaptic refinement through release of gliotransmitters and/or synaptogenic factors. Selective manipulation of MC calcium signaling during this period of remarkable refinement will help to further define their roles in the development of distinct retinal circuits.
A structure at the back of the eye known as the retina is essential for vision . When light hits the retina , cells called neurons produce electrical signals that lead to the release of chemicals known as neurotransmitters . When these chemicals reach a neighboring neuron , a corresponding electrical signal is produced in this cell . In this way , information about what we can see is ultimately transmitted to the brain . The retina also contains cells that are not neurons , such as Müller glial cells . These cells span the thickness of the retina , and appear well placed to interact with all of the different types of neuron in the retina . Other types of glial cells help the neural circuits in the brain to develop , but it is not clear whether Müller cells perform the same role in the developing retina . Newborn mice do not open their eyes until around two weeks after they are born , during which time their retina continues to develop . The retinal neurons are already active throughout this period , and spontaneously generate periodic bursts of electrical activity that spreads across the developing retina in waves . Now , Rosa , Bos et al . show that in newborn mice , these waves also trigger brief , or ‘transient’ , increases in the concentration of calcium ions inside Müller cells . Exactly how the Müller cells respond depends on which neurotransmitters are released during waves . A few days before the mice open their eyes , the number of calcium transients in Müller cells decreases sharply . At the same time , neurons continue to spontaneously release waves of one particular neurotransmitter called glutamate . Rosa , Bos et al . used a sensor that showed where glutamate is found in the developing retina . This revealed that the decrease in calcium transients as the retina matures is due to less glutamate reaching the Müller cells . These findings reveal that Müller cells are involved in the spontaneous electrical activity seen in the retina during a critical period of retinal development . The next challenge is to determine how this neuronal-glial cell signaling helps the retina to mature .