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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Article
  • Peer Reviewed
UC Berkeley Previously Published Works (2021)
Throughout the nervous system, the organization of excitatory and inhibitory synaptic inputs within a neuron's receptive field shapes its output computation. In some cases, multiple motifs of synaptic organization can contribute to a single computation. Here, we compare two of these mechanisms performed by two morphologically distinct retinal direction-selective ganglion cells (DSGCs): directionally tuned inhibition and spatially offset inhibition. Using drifting stimuli, we found that DSGCs that have asymmetric dendrites exhibited stronger directionally tuned inhibition than symmetric DSGCs. Using stationary stimuli to map receptive fields, we found that DSGCs with both symmetric and asymmetric dendrites exhibited similar spatially offset inhibition. Interestingly, we observed that excitatory and inhibitory synapses for both cell types were locally correlated in strength. This result indicates that in the mouse retina, dendritic morphology influences the amount of tuned inhibition attained through asymmetric wiring but does not dictate the synaptic organization of excitation relative to inhibition.
    Cover page: Dendrite morphology minimally influences the synaptic distribution of excitation and inhibition in retinal direction selective ganglion cells
    • Thesis
    • Peer Reviewed
    UC Berkeley Electronic Theses and Dissertations (2021)

    Retinal ganglion cells (RGCs) represent the output computations of the visual world. In the mouse, they represent >30 parallel channels of visual processing, encoding both image-forming and non-image forming features. The dendrites of RGCs are considered essential in ensuring that the downstream visual system receives a full depiction of the sampled visual field. Different retinal ganglion cell types have evolved a multitude of dendritic arbor architectures that allow them to efficiently encode the spatial and temporal features of the visual scene that they are tuned to. Despite this fundamental role of dendritic morphology, there are relatively few studies that directly test whether different dendritic morphologies lead to variations in the wiring and resulting computations within a neural circuit.

    This main body of this work has aimed to address this question in a well-defined neural circuit in the retina that is responsible for our ability to detect the direction an object moves in the visual world. Direction selectivity is a neural computation where a directionally selective retinal ganglion cell (DSGC), one of the output neurons of the retina whose axons comprise the optic nerve, fire more action potentials in response to motion in one direction, versus motion in the opposite direction. Multiple presynaptic mechanisms involving the specific wiring of excitatory and inhibitory inputs onto DSGC dendrites have been postulated to contribute to the direction selectivity computation. Additionally, postsynaptic computations within the DSGC dendrites have been postulated to sharpen their directional tuning

    Here, we explore how DSGC dendrites contribute to both the presynaptic organization of excitatory and inhibitory inputs, and the postsynaptic contribution to directional tuning. First, we show that visual experience influences the dendritic orientation in a population of asymmetric ventral preferring DSGCs (vDSGCs) whose dendrites point ventrally. By comparing the tuning of normally versus dark-reared vDSGCs, we find that their tuning to ventral motion is preserved regardless of their dendritic orientation. This is due to the persistence of asymmetric wiring of inhibition in dark-reared vDSGCs. However, we find that the ventral orientation of vDSGC dendrites is necessary for their postsynaptic directional computation, which occurs in the absence of inhibitory input. Hence, in vDSGCs, dendritic morphology dictates postsynaptic but not presynaptic mechanisms for directional computation.

    Second, we show that dendritic morphology, across two distinct populations of DSGCs, does not determine the organization of presynaptic inputs. By comparing the excitatory and inhibitory receptive fields across two morphologically distinct DSGC subtypes, we find that although asymmetric DSGCs exhibit greater tuning of their inhibitory input in response to a moving stimulus, compared to symmetric DSGCs, the synaptic organization of excitation relative to inhibition is comparable across cell types. Hence, DSGC dendritic morphology does not dictate the organization of excitatory and inhibitory synaptic inputs relative to each other.

      Cover page: The Role of Dendrites in the Organization of Functional Neural Circuits for Motion Detection in the Retina
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2020)
      Changes in dendritic morphology in response to activity have long been thought to be a critical component of how neural circuits develop to properly encode sensory information. Ventral-preferring direction-selective ganglion cells (vDSGCs) have asymmetric dendrites oriented along their preferred direction, and this has been hypothesized to play a critical role in their tuning. Here we report the surprising result that visual experience is critical for the alignment of vDSGC dendrites to their preferred direction. Interestingly, vDSGCs in dark-reared mice lose their inhibition-independent dendritic contribution to direction-selective tuning while maintaining asymmetric inhibitory input. These data indicate that different mechanisms of a cell's computational abilities can be constructed over development through divergent mechanisms.
        Cover page: Visual Experience Influences Dendritic Orientation but Is Not Required for Asymmetric Wiring of the Retinal Direction Selective Circuit
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2015)
        Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2's isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development.
          Cover page: Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination
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