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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2014)

Across the developing nervous system, immature networks generate spontaneous activity that is highly correlated amongst neighboring cells, which is required for the correct establishment of adult neural circuits. Remarkably, correlated activity persists following disruption of the underlying circuits that mediate it, indicating that plasticity mechanisms exist to ensure correlated activity is maintained. Here, we examine this phenomenon in the developing mouse retina, where correlated activity is mediated by cholinergic transmission and propagates across the retina as a wave. The absence of cholinergic signaling leads to the generation of "recovered" waves that propagate through a distinct, gap junction mediated circuit. Our findings show that stimulation of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) facilitates recovery of correlated activity in the absence of cholinergic waves, which results in the emergence of a light-sensitive network. We tested whether pharmacological blockade of cholinergic waves altered retinal light-response properties. We observed an increase in the duration of light-evoked activity and number of light-responsive cells, which arose from signaling via gap junctions. These observations suggest that electrical coupling of ipRGCs increases in the absence of cholinergic input, allowing melanopsin-driven signals to propagate to other neurons. Furthermore, we show that light-sensitive waves are strongly modulated by dopamine signaling--a potent neuromodulator of gap junction coupling. We determine that this light-sensitive wave circuit is present but latent in wild type retina, where it is usually suppressed by a combination of cholinergic and dopaminergic signaling. Our observations indicate that dopamine signaling acts as a switch for network reconfiguration, where high dopamine silences the light-sensitive, gap junction coupled network under cholinergic waves and reduced dopamine activates it in the absence of cholinergic waves. We conclude that the wiring diagram of the developing retina includes several overconnected circuits, in which some circuits are closed and others activated depending on the internal state of the system.

    Cover page: Mechanisms of Circuit Plasticity in the Developing Retina
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2016)

    Unlabelled

    Before the maturation of rod and cone photoreceptors, the developing retina relies on light detection by intrinsically photosensitive retinal ganglion cells (ipRGCs) to drive early light-dependent behaviors. ipRGCs are output neurons of the retina; however, they also form functional microcircuits within the retina itself. Whether ipRGC microcircuits exist during development and whether they influence early light detection remain unknown. Here, we investigate the neural circuit that underlies the ipRGC-driven light response in developing mice. We use a combination of calcium imaging, tracer coupling, and electrophysiology experiments to show that ipRGCs form extensive gap junction networks that strongly contribute to the overall light response of the developing retina. Interestingly, we found that gap junction coupling was modulated by spontaneous retinal waves, such that acute blockade of waves dramatically increased the extent of coupling and hence increased the number of light-responsive neurons. Moreover, using an optical sensor, we found that this wave-dependent modulation of coupling is driven by dopamine that is phasically released by retinal waves. Our results demonstrate that ipRGCs form gap junction microcircuits during development that are modulated by retinal waves; these circuits determine the extent of the light response and thus potentially impact the processing of early visual information and light-dependent developmental functions.

    Significance statement

    Light-dependent functions in early development are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Here we show that ipRGCs form an extensive gap junction network with other retinal neurons, including other ipRGCs, which shapes the retina's overall light response. Blocking cholinergic retinal waves, which are the primary source of neural activity before maturation of photoreceptors, increased the extent of ipRGC gap junction networks, thus increasing the number of light-responsive cells. We determined that this modulation of ipRGC gap junction networks occurs via dopamine released by waves. These results demonstrate that retinal waves mediate dopaminergic modulation of gap junction networks to regulate pre-vision light responses.
      Cover page: Retinal Waves Modulate an Intraretinal Circuit of Intrinsically Photosensitive Retinal Ganglion Cells
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2013)
      Before the onset of sensory transduction, developing neural circuits spontaneously generate correlated activity in distinct spatial and temporal patterns. During this period of patterned activity, sensory maps develop and initial coarse connections are refined, which are critical steps in the establishment of adult neural circuits. Over the last decade, there has been substantial evidence that altering the pattern of spontaneous activity disrupts refinement, but the mechanistic understanding of this process remains incomplete. In this review, we discuss recent experimental and theoretical progress toward the process of activity-dependent refinement, focusing on circuits in the visual, auditory, and motor systems. Although many outstanding questions remain, the combination of several novel approaches has brought us closer to a comprehensive understanding of how complex neural circuits are established by patterned spontaneous activity during development.
        Cover page: A Role for Correlated Spontaneous Activity in the Assembly of Neural Circuits
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2014)
        The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons.
          Cover page: Synapse elimination and learning rules co-regulated by MHC class I H2-Db
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